tag:blogger.com,1999:blog-68219483295412124152024-03-20T15:13:12.492-04:00NIHilist's ImmunologyHow Immune System worksDavid Usharaulihttp://www.blogger.com/profile/02668672470276307921noreply@blogger.comBlogger420125tag:blogger.com,1999:blog-6821948329541212415.post-75354401870409439592023-01-11T19:12:00.000-05:002023-01-11T19:12:26.274-05:00If T cell clones are so diverse, what prevents anti-tumor immune response?<div style="text-align: justify;">Identifying cancer and pathogen-specific epitopes or TCRs may sound intuitive, but it is a futile approach. Diversity of T cell or B cell clones guarantees that the adaptive immune system will always have relevant clones to detect cancer or pathogen. </div><div style="text-align: justify;"><br /></div><div style="text-align: justify;">Epitopes have no meaning attached to them with one exception. It is when the said epitope is self. Each body will have different sets of self-epitopes. Every self-epitopes relevant for host's survival are encoded in the thymus, and thymic Tregs are trained to prevent any T cell activity against those epitopes in the periphery. This is called tolerance, and it is antigen[epitope]-specific. <br /></div><div style="text-align: left;"><br /></div><div style="text-align: justify;">Then what prevents effective responses to cancers or pathogens? It is commonly but mistakenly believed that Tregs prevent effective T or B cell responses to cancers or pathogens. But Tregs only prevent anti-self response, and it is epitope-specific action. So, by definition, if Tregs do their job as required, we cannot blame them. But it has nothing to do with cancer or pathogens, which obviously have other epitopes different from self, we call nonself. So, if cancer cells or pathogens express nonself epitopes that are always detected by adaptive immune system, why not everyone can fight it off effectively? <br /></div><div style="text-align: left;"><br /></div><div style="text-align: justify;">This is because T cells themselves prevent it. Yes, T cells, not Tregs, prevent effective response to cancers or pathogens in certain conditions. What are those conditions? These are condition when polarized T helper cells prevent other T cells functions. Polarization is a pathological state. A Polarized T cell's effect on other T cells is epitope non-specific, meaning, a polarized T helper cell specific to cancer or pathogen nonself epitope A will prevent T cells specific to epitope B, C, D, E, F, etc., to function properly. It is exactly Treg's job to shut down those polarized T helper cells to allow other T cells to manifest their functions and get rid of either cancer or pathogen. And Treg do it, as we already said, epitope-specific manner. <br /></div><div style="text-align: left;"><br /></div><div style="text-align: justify;">For this reason, it is not so important to identify any cancer or pathogen-specific nonself epitope, but rather to identify an epitope that could activate polarized T helper cells. <br /></div><div style="text-align: justify;"><br /></div><div style="text-align: justify;">To make things even more complicated, one may ask if Tregs are self-specific and act epitope-specific manner, how can Tregs shut down polarized T helper cells that are nonself-specific? It is possible because Tregs are cross-reactive and can inhibit only those polarized T helper cells which share TCR specificity with Tregs. <br /></div><div style="text-align: justify;"><br /></div><div style="text-align: justify;">In other words, control of self-tolerance and control of effective anti-nonself response are one and the same. </div><div style="text-align: justify;"><br /></div><div style="text-align: justify;">These are 3 papers that together provide a full discussion related to the SPIRAL model we have developed to explain how Tregs work within an adaptive immune system:</div><div style="text-align: justify;"> </div><div style="text-align: justify;"> </div><div style="text-align: justify;">Concurrent cross-reactivity of microbiota-derived epitopes to both self and pathogens may underlie the "Hygiene hypothesis" </div><div style="text-align: justify;"> </div><div style="text-align: justify;"><a href="https://onlinelibrary.wiley.com/doi/10.1111/sji.12708" target="_blank">https://onlinelibrary.wiley.com/doi/10.1111/sji.12708</a> <br /></div><div style="text-align: center;"> </div><div style="text-align: justify;"><br /></div><div style="text-align: justify;">Could cross-reactivity rescue Foxp3+ regulatory T cell precursors from thymic deletion? </div><div style="text-align: justify;"> </div><div style="text-align: justify;"><a href="https://onlinelibrary.wiley.com/doi/10.1111/sji.12940 " target="_blank">https://onlinelibrary.wiley.com/doi/10.1111/sji.12940 </a><br /></div><div style="text-align: justify;"> </div><div style="text-align: justify;"> </div><div style="text-align: justify;"> </div><div style="text-align: justify;">Microbiota-Specific Foxp3+ Regulatory T Cells Could Control Pathological T Helper Responses</div><div style="text-align: justify;"> </div><div style="text-align: justify;"><a href="https://www.dl.begellhouse.com/journals/2ff21abf44b19838,40a32b197f7156bc,7988864072d2c7c6.html " target="_blank">https://www.dl.begellhouse.com/journals/2ff21abf44b19838,40a32b197f7156bc,7988864072d2c7c6.html </a><br /></div><div style="text-align: left;"><br /></div><div style="text-align: left;"><br /></div><div style="text-align: left;"> <br /></div><div style="text-align: left;"> <br /></div><div style="text-align: left;"><br /></div><div style="text-align: left;"> <br /></div><div style="text-align: left;"><br /></div><div style="text-align: left;"><br /></div><div style="text-align: left;"><br /></div><div style="text-align: left;"><br /><br /></div>David Usharaulihttp://www.blogger.com/profile/02668672470276307921noreply@blogger.com0tag:blogger.com,1999:blog-6821948329541212415.post-48510925052181261542020-09-18T16:33:00.001-04:002020-09-18T16:52:24.504-04:00A specific bacteria-infecting virus, bacteriophage, found in gut microflora, augments anti-tumor T cell immunity <p style="text-align: justify;"><span style="font-size: large;"><span style="font-family: inherit;">Molecular mimicry between microbial and host's antigens could contribute to autoimmunity but also to the protection against tumors through epitope cross-reactivity. A new study in journal Science indicates that those <a href="https://science.sciencemag.org/content/369/6506/936">cross-reactive epitopes</a> could come from viruses that infect endogenous microbial species. </span></span></p><p style="text-align: justify;"><span style="font-size: large;"><span style="font-family: inherit;">In this study the authors made a surprising observation that only certain <i>Enterococcus hirae</i> microbial strains (<i>E. hirae</i> 13144 or IGR11) augmented anti-cancer effect in experimental cancer model.</span></span></p><p style="text-align: justify;"><span style="font-size: large;"><span style="font-family: inherit;"> </span></span></p><p style="text-align: justify;"><span style="font-size: large;"><span style="font-family: inherit;"></span></span></p><div class="separator" style="clear: both; text-align: center;"><span style="font-size: large;"><a href="https://1.bp.blogspot.com/-dTJoDHJNJq0/X2UYCqZVvwI/AAAAAAAAEhI/DHiJmFzDIxMstfXBgsJ5sF5El233CgYRwCLcBGAsYHQ/s1665/Screenshot%2B%25281940%2529.png" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="518" data-original-width="1665" height="200" src="https://1.bp.blogspot.com/-dTJoDHJNJq0/X2UYCqZVvwI/AAAAAAAAEhI/DHiJmFzDIxMstfXBgsJ5sF5El233CgYRwCLcBGAsYHQ/w640-h200/Screenshot%2B%25281940%2529.png" width="640" /></a></span></div><span style="font-size: large;"><br /> </span><p></p><p style="text-align: justify;"><span style="font-size: large;"><span style="font-family: inherit;">Next, the authors showed that this biological activity was linked to one dominant epitope, TSLARFANI, derived from TMP protein that originated in 39.2-kb prophage only in those specific <i>E. hirae</i> strains. Mice immunized with heat-inactivated <i>E. hirae</i> 13144 strain, or peptide TSLARFANI, or irrelevant <i>E.coli</i> engineered to express TMP, all augmented anti-cancer effect. </span></span></p><p style="text-align: justify;"><span style="font-size: large;"><span style="font-family: inherit;"> </span></span></p><p style="text-align: justify;"><span style="font-size: large;"><span style="font-family: inherit;"></span></span></p><div class="separator" style="clear: both; text-align: center;"><span style="font-size: large;"><a href="https://1.bp.blogspot.com/-sbaIG7gkmn4/X2UYK0b3RNI/AAAAAAAAEhM/3nqxd4Df2igGJ2-wI00FLwbgZa157UAJQCLcBGAsYHQ/s1716/Screenshot%2B%25281941%2529.png" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="801" data-original-width="1716" height="298" src="https://1.bp.blogspot.com/-sbaIG7gkmn4/X2UYK0b3RNI/AAAAAAAAEhM/3nqxd4Df2igGJ2-wI00FLwbgZa157UAJQCLcBGAsYHQ/w640-h298/Screenshot%2B%25281941%2529.png" width="640" /></a></span></div><span style="font-size: large;"><br /> </span><p></p><p style="text-align: justify;"><span style="font-size: large;"><span style="font-family: inherit;">Mechanistically, the authors showed that epitope, GSLARFRNI, derived from cancer cells used in these experiments, was recognized by the same CD8 T cells which labeled with TSLARFANI epitope tetramers confirming cross-reactivity between these 2 epitopes.</span></span></p><p style="text-align: justify;"><span style="font-size: large;"><span style="font-family: inherit;"> </span></span></p><p style="text-align: justify;"><span style="font-size: large;"><span style="font-family: inherit;"></span></span></p><div class="separator" style="clear: both; text-align: center;"><span style="font-size: large;"><a href="https://1.bp.blogspot.com/-4jQaMxWQFWk/X2UYTj8H7SI/AAAAAAAAEhU/BNx56Ms_blwelTw_scgruUH8NJVq7XGUACLcBGAsYHQ/s1719/Screenshot%2B%25281942%2529.png" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="565" data-original-width="1719" height="210" src="https://1.bp.blogspot.com/-4jQaMxWQFWk/X2UYTj8H7SI/AAAAAAAAEhU/BNx56Ms_blwelTw_scgruUH8NJVq7XGUACLcBGAsYHQ/w640-h210/Screenshot%2B%25281942%2529.png" width="640" /></a></span></div><span style="font-size: large;"><br /> </span><p></p><p style="text-align: justify;"><span style="font-size: large;"><span style="font-family: inherit;">In summary, this study suggests that microbiota and bacteriophages they carry represent new modality in fight against cancer. In this study overall anti-tumor effect is modest</span> but we need to take into account that this is an effect of just one cross-reactive epitope in one type of MHC inbred mice, and it is likely that many other epitopes will be involved in outbred species such as humans. However, it is still extremely hard to do such analysis in humans in real world scenario due to lack of exact knowledge about human microbiota strains and poor reliability and performances of available bioinformatics approaches. However, once the mechanistic principles underlying anti-cancer effects are uncovered and accepted, then it is much easier to move the field forward. <br /></span></p><p style="text-align: justify;"><span style="font-size: large;"><span style="font-family: inherit;">posted by David Usharauli <br /></span></span></p>David Usharaulihttp://www.blogger.com/profile/02668672470276307921noreply@blogger.com4tag:blogger.com,1999:blog-6821948329541212415.post-360921215904227732020-08-06T18:58:00.000-04:002020-09-18T16:34:14.926-04:00Is it possible to engineer Foxp3+ Tregs from primary T cells?<div style="text-align: justify;"><span style="font-family: helvetica;">Here is the most recent paper that claims that they can do it. It was published in <a href="https://stm.sciencemag.org/content/12/546/eaay6422">Science Translational Medicine</a>. This is fairly respectable journal run by Science. This research group is so confident in their data that they even set up a <a href="https://www.biospace.com/article/gentibio-launches-with-20-million-seed-funding-from-novartis-and-others/">new biotech company</a> to commercialize their approach. I am going to examine how strong are their claims.</span></div><div style="text-align: justify;"><span style="font-family: helvetica;"><br /></span></div><div style="text-align: justify;"><span style="font-family: helvetica;">Here is a short description what they did: they used a combination of specific nuclease (TALEN) and virus (AAV6) to insert a new promoter into Foxp3 gene in an in vitro activated T cells. They called these Tregs edTregs.<br /></span></div><div style="text-align: justify;"><span style="font-family: helvetica;"><br /></span></div><div style="text-align: justify;"><table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="height: 229px; margin-left: auto; margin-right: auto; width: 512px;"><tbody><tr><td style="text-align: center;"><a href="https://1.bp.blogspot.com/-lXShtkgSL6Q/Xyx0FFxWghI/AAAAAAAAEck/mPwn50G9pHEGDQPp8qQcRD2sAdQTBkBUwCLcBGAsYHQ/s2117/Screenshot%2B%25281928%2529.png" style="display: block; margin-left: auto; margin-right: auto; padding: 1em 0px;"><img border="0" data-original-height="734" data-original-width="2117" height="223" src="https://1.bp.blogspot.com/-lXShtkgSL6Q/Xyx0FFxWghI/AAAAAAAAEck/mPwn50G9pHEGDQPp8qQcRD2sAdQTBkBUwCLcBGAsYHQ/w640-h223/Screenshot%2B%25281928%2529.png" width="640" /></a></td></tr><tr><td class="tr-caption" style="text-align: center;"><span style="font-family: helvetica;">insertion of MND promoter</span><br /></td></tr></tbody></table><span style="font-family: helvetica;"><br /></span></div><div style="text-align: justify;"><span style="font-family: helvetica;"><br /></span></div><div style="text-align: justify;"><span style="font-family: helvetica;">The edTregs displayed very similar functionality known to occur in thymus-derived Tregs (tTregs) such as no or limited expression of IL-2 and other cytokines in an in vitro stimulation assays. <br /></span></div><div style="text-align: justify;"><span style="font-family: helvetica;"><br /></span></div><div style="text-align: justify;"><span style="font-family: helvetica;"><br /></span></div><div style="text-align: justify;"><span style="font-family: helvetica;"><br /></span></div><div style="text-align: justify;"><div class="separator" style="clear: both;"><a href="https://1.bp.blogspot.com/-TuGUsUkN9Us/Xyx3oeWW0TI/AAAAAAAAEdk/fRm4DVwkDE8crUhWOw1U0pjGHGwWcWF4ACLcBGAsYHQ/s1280/Screenshot%2B%25281922%2529.png" style="display: block; padding: 1em 0px;"><img border="0" data-original-height="1276" data-original-width="1280" src="https://1.bp.blogspot.com/-TuGUsUkN9Us/Xyx3oeWW0TI/AAAAAAAAEdk/fRm4DVwkDE8crUhWOw1U0pjGHGwWcWF4ACLcBGAsYHQ/s640/Screenshot%2B%25281922%2529.png" width="640" /></a></div><span style="font-family: helvetica;"><br /></span></div><div style="text-align: justify;"><span style="font-family: helvetica;">The edTregs were suppressive towards effector T cells in a proliferation assay as should be expected from tTregs. Moreover this essential function required endogenous Foxp3 activity as edTregs from IPEX individuals with a defective Foxp3 gene did not show suppression.<br /></span></div><div style="text-align: justify;"><span style="font-family: helvetica;"><br /></span></div><div style="text-align: justify;"><span style="font-family: helvetica;"><br /></span></div><div style="text-align: justify;"><span style="font-family: helvetica;"><br /></span></div><div style="text-align: justify;"><span style="font-family: helvetica;"><br /></span></div><div style="text-align: justify;"><table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto;"><tbody><tr><td style="text-align: center;"><a href="https://1.bp.blogspot.com/-Ew2t4r5QX7c/Xyx4szPAZZI/AAAAAAAAEeg/GWtjRrXHwTwlSh40KXEAwKRQ99LrinVQgCLcBGAsYHQ/s1470/Screenshot%2B%25281923%2529.png" style="display: block; margin-left: auto; margin-right: auto; padding: 1em 0px;"><img border="0" data-original-height="1011" data-original-width="1470" height="352" src="https://1.bp.blogspot.com/-Ew2t4r5QX7c/Xyx4szPAZZI/AAAAAAAAEeg/GWtjRrXHwTwlSh40KXEAwKRQ99LrinVQgCLcBGAsYHQ/w512-h352/Screenshot%2B%25281923%2529.png" width="512" /></a></td></tr><tr><td class="tr-caption" style="text-align: center;"><span style="font-family: helvetica;">proliferation assay</span><br /></td></tr></tbody></table><span style="font-family: helvetica;"><br /></span></div><div style="text-align: justify;"><span style="font-family: helvetica;"><br /></span></div><div style="text-align: justify;"><table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto;"><tbody><tr><td style="text-align: center;"><a href="https://1.bp.blogspot.com/-PLpm53NODs0/Xyx6az71wII/AAAAAAAAEes/9lV_ukWYS6I3oMm7KovaCs2XNVtgdQyYwCLcBGAsYHQ/s981/Screenshot%2B%25281925%2529.png" style="display: block; margin-left: auto; margin-right: auto; padding: 1em 0px;"><img border="0" data-original-height="659" data-original-width="981" height="220" src="https://1.bp.blogspot.com/-PLpm53NODs0/Xyx6az71wII/AAAAAAAAEes/9lV_ukWYS6I3oMm7KovaCs2XNVtgdQyYwCLcBGAsYHQ/w328-h220/Screenshot%2B%25281925%2529.png" width="328" /></a></td></tr><tr><td class="tr-caption" style="text-align: center;"><br /></td></tr></tbody></table><span style="font-family: helvetica;"><br /></span></div><div style="text-align: justify;"><span style="font-family: helvetica;">However, edTregs were significantly different from tTregs in Treg-specific demethylated region (TSDR). The point is it is now accepted that Treg identity is not established solely because of Foxp3 expression but requires specific and selective epigenetic modification within and outside of Foxp3 gene. Nonetheless, in <i>in vitro</i> assays, edTregs behaved as <i>bona fide</i> tTregs. <br /></span></div><div style="text-align: justify;"><table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto;"><tbody><tr><td style="text-align: center;"><a href="https://1.bp.blogspot.com/-NyVUKKH4Lfc/Xyx7IO_aUUI/AAAAAAAAEe0/zd7nv88VnKoWFfwBVzYyZA4Kl2KtGu9vACLcBGAsYHQ/s935/Screenshot%2B%25281924%2529.png" style="display: block; margin-left: auto; margin-right: auto; padding: 1em 0px;"><img border="0" data-original-height="761" data-original-width="935" height="334" src="https://1.bp.blogspot.com/-NyVUKKH4Lfc/Xyx7IO_aUUI/AAAAAAAAEe0/zd7nv88VnKoWFfwBVzYyZA4Kl2KtGu9vACLcBGAsYHQ/w410-h334/Screenshot%2B%25281924%2529.png" width="410" /></a></td></tr><tr><td class="tr-caption" style="text-align: center;"><br /></td></tr></tbody></table><span style="font-family: helvetica;"><br /></span></div><div style="text-align: justify;"><span style="font-family: helvetica;"><br /></span></div><div style="text-align: justify;"><span style="font-family: helvetica;">What about in vivo? There the story gets a little bit murky. The authors used two models to assess edTregs in vivo. First, they co-transferred edTregs with effector T cells into immunodeficient mice to assess if edTregs could prevent graft versus host disease (GvHD). They do see reduction of mice mortality with edTregs. <br /></span></div><div style="text-align: justify;"><span style="font-family: helvetica;"><br /></span></div><div style="text-align: justify;"><span style="font-family: helvetica;"><div class="separator" style="clear: both;"><a href="https://1.bp.blogspot.com/-YlxIkswAkJw/Xyx93x4-bxI/AAAAAAAAEfA/NRM2zCxqMFwaSyCzLmJ9Jk9lRq1hqOm2gCLcBGAsYHQ/s2367/Screenshot%2B%25281926%2529.png" style="display: block; padding: 1em 0px;"><img border="0" data-original-height="648" data-original-width="2367" height="219" src="https://1.bp.blogspot.com/-YlxIkswAkJw/Xyx93x4-bxI/AAAAAAAAEfA/NRM2zCxqMFwaSyCzLmJ9Jk9lRq1hqOm2gCLcBGAsYHQ/w800-h219/Screenshot%2B%25281926%2529.png" width="800" /></a></div>However, there are some inconsistency between experiments describing GvHD model. In one set of experiments it produced 100% lethality by day 21 (see below, red line) while in other set of experiments it produced only 20% lethality (see above, red line). <br /></span></div><div style="text-align: justify;"><span style="font-family: helvetica;"><br /><table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto;"><tbody><tr><td style="text-align: center;"><a href="https://1.bp.blogspot.com/-R-Y5ytY_w18/Xyx959F7GmI/AAAAAAAAEfI/fpvZQpfGGjoF4otUHK9vcKOMy4amNNrIQCLcBGAsYHQ/s1565/Screenshot%2B%25281929%2529.png" style="display: block; margin-left: auto; margin-right: auto; padding: 1em 0px;"><img border="0" data-original-height="854" data-original-width="1565" height="223" src="https://1.bp.blogspot.com/-R-Y5ytY_w18/Xyx959F7GmI/AAAAAAAAEfI/fpvZQpfGGjoF4otUHK9vcKOMy4amNNrIQCLcBGAsYHQ/w410-h223/Screenshot%2B%25281929%2529.png" width="410" /></a></td></tr><tr><td class="tr-caption" style="text-align: center;"><br /></td></tr></tbody></table>Such inconsistency casts doubts about edTregs ability to inhibit effector T cells <i>in vivo</i> and could explain why the authors did not see much difference in GvHD scores with or without edTregs (see below).</span><br /><br /><span style="font-family: helvetica;"><table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto;"><tbody><tr><td style="text-align: center;"><img border="0" data-original-height="1301" data-original-width="1370" height="608" src="https://1.bp.blogspot.com/-HWaFsFPvn1k/Xyx953q6wEI/AAAAAAAAEfM/nssJjQ8-21Al5nbujJ13Ao1Ngp3Lils_QCLcBGAsYHQ/w641-h608/Screenshot%2B%25281930%2529.png" style="margin-left: auto; margin-right: auto;" width="641" /></td></tr><tr align="left"><td class="tr-caption"><br /></td></tr></tbody></table></span><span style="font-family: helvetica;"><table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto;"><tbody><tr><td style="text-align: center;"><br /><div style="text-align: left;"><span style="font-family: helvetica;"> </span><br /></div><div style="text-align: left;"><span style="font-family: helvetica;">This
could also explain why the authors did not see improvement in brain
inflammation in mice EAE model when co-transferring antigen-specific edTregs with
effector T cells.</span><br /></div><a href="https://1.bp.blogspot.com/-9r-ITphwPGU/Xyx93_8wBDI/AAAAAAAAEfE/Dj3LDk49O0gco9JyXtXoZOKUPE8k_Jc8QCLcBGAsYHQ/s1271/Screenshot%2B%25281927%2529.png" style="display: block; margin-left: auto; margin-right: auto; padding: 1em 0px;"><img border="0" data-original-height="1255" data-original-width="1271" height="506" src="https://1.bp.blogspot.com/-9r-ITphwPGU/Xyx93_8wBDI/AAAAAAAAEfE/Dj3LDk49O0gco9JyXtXoZOKUPE8k_Jc8QCLcBGAsYHQ/w513-h506/Screenshot%2B%25281927%2529.png" width="513" /></a></td></tr><tr><td class="tr-caption" style="text-align: center;"><br /></td></tr></tbody></table></span><span style="font-family: helvetica;"> </span></div><div style="text-align: justify;"><span style="font-family: helvetica;">In summary, this paper has done a lot of interesting in vitro work trying to convince us that their edTregs work as intended. However, in vivo work lacks consistency. It is not surprising. It has been known for some time now that Tregs behave differently <i>in vitro</i> vs. <i>in vivo</i>. Suppression <i>in vivo</i> appears to be strictly antigen-specific phenomenon unlike <i>in vitro</i> where it could be observed antigen-nonspecific manner (even though Treg activation in itself still require presence of cognate antigen). <br /></span></div><div style="text-align: justify;"><span style="font-family: helvetica;"><br /></span></div><div style="text-align: justify;"><span style="font-family: helvetica;"><br /></span></div><div style="text-align: justify;"><span style="font-family: helvetica;">posted by David Usharauli<br /></span></div><div style="text-align: justify;"><span style="font-family: helvetica;"><br /></span></div><div style="text-align: justify;"><span style="font-family: helvetica;"> <br /></span></div>David Usharaulihttp://www.blogger.com/profile/02668672470276307921noreply@blogger.com2tag:blogger.com,1999:blog-6821948329541212415.post-11896996020947230742020-04-15T16:53:00.000-04:002020-04-15T16:53:51.547-04:00Do Tregs inhibit or promote allergic responses? How to avoid data misinterpretation <div style="text-align: justify;">
Foxp3+ regulatory T cells (Tregs) are the most essential component of the immune system. No other cell population, taken singularly, have such an indispensable role in the proper functioning of the immune system. Tregs are known to inhibit inappropriate immune response against self-antigens, commensal microbiota or even nonself pathogens. I strongly believe that data are very clear about it.</div>
<div style="text-align: justify;">
<br /></div>
<div style="text-align: justify;">
So, when I see a well-designed research paper showing something contrary I immediately want to understand its details. Take this <a href="https://www.jci.org/articles/view/132249" target="_blank">new paper</a> from The Journal of Clinical Investigation (JCI) as an example. It claims and data its provided is pretty solid that removal of a subset of Tregs called T follicular regulatory cells (Tfr) from the immune system in <i>Foxp3-cre Bcl6-fl/fl</i> mice paradoxically reduces, rather than increases, peanut-specific IgE responses. </div>
<div style="text-align: justify;">
<br /></div>
<div class="separator" style="clear: both; text-align: center;">
<a href="https://1.bp.blogspot.com/-BeIlhTYq2js/Xpdqf2pR6KI/AAAAAAAAEaM/y2qTTzOfMOQA3fafNGXtQuFFNPii9OwuQCLcBGAsYHQ/s1600/Screenshot%2B%25281903%2529.png" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="828" data-original-width="829" height="319" src="https://1.bp.blogspot.com/-BeIlhTYq2js/Xpdqf2pR6KI/AAAAAAAAEaM/y2qTTzOfMOQA3fafNGXtQuFFNPii9OwuQCLcBGAsYHQ/s320/Screenshot%2B%25281903%2529.png" width="320" /></a></div>
<br />
<div class="separator" style="clear: both; text-align: left;">
<br /></div>
<div class="separator" style="clear: both; text-align: justify;">
And if you think maybe their knockout mice are some kind of weirdos, not really. Their model also shows that total IgE is increasing as expected. So, the system the authors are using is within acceptable norms. </div>
<div class="separator" style="clear: both; text-align: justify;">
<br /></div>
<div class="separator" style="clear: both; text-align: center;">
<a href="https://1.bp.blogspot.com/--nXI_tQNe0s/Xpdqg3J_MkI/AAAAAAAAEaQ/z8WUgD4hl5wvahM1L1gFR_1gQjDPiE-lwCLcBGAsYHQ/s1600/Screenshot%2B%25281904%2529.png" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="857" data-original-width="1120" height="305" src="https://1.bp.blogspot.com/--nXI_tQNe0s/Xpdqg3J_MkI/AAAAAAAAEaQ/z8WUgD4hl5wvahM1L1gFR_1gQjDPiE-lwCLcBGAsYHQ/s400/Screenshot%2B%25281904%2529.png" width="400" /></a></div>
<div class="separator" style="clear: both; text-align: justify;">
<br /></div>
<div style="text-align: justify;">
The authors then went on to show that IL-10 derived from Tfr cells are important for promoting peanut allergy-producing IgE production. </div>
<div style="text-align: justify;">
<br /></div>
<div style="text-align: justify;">
These results are totally against the whole paradigm about the role of Tfr cells and even IL-10 because the authors speculating that we need to block IL-10 to reduce peanut allergy rather than inject IL-10 to inhibit it, as everyone thinks currently (IL-10 is lesser understood cytokine but it is generally accepted as an immunosuppressant.)</div>
<div style="text-align: justify;">
<br /></div>
<div style="text-align: justify;">
So, how to interpret these results? Basically, what's going on? Is there a way to interpret these results within the confines of the established concept?</div>
<div style="text-align: justify;">
<br /></div>
<div style="text-align: justify;">
I think there is at least one possibility the authors did not consider in their discussions. Here the authors are looking for primary adaptive T/B cell response to a novel antigen, peanut antigen in this case. In this scenario, peanut allergy promoting IgE response is clearly reduced without Tfr cells. But at the same time, the level of total IgE (representing unknown antigen-specific IgE responses) has increased. We could say that total IgE is derived from an already established memory T/B system rather than from primary immune response as peanut IgE is. This memory T/B/plasma cells then boost total IgE levels when the brakes applied by Tfrs are removed. But the same principle does not apply for primary T/B response to peanut allergen. Why is that? It is possible that the absence of Tfr specifically messes up with primary T/B cooperation. It is not a direct effect but rather indirect due to the activation of other components of the immune system when brakes are removed. So, primary T/B responses will be undermined by a lack of Tfr cells and it would appear if Tfr cells were promoting primary IgE responses and their absence reduced IgE production. </div>
<div style="text-align: justify;">
<br /></div>
<div style="text-align: justify;">
The correct interpretation is essential, especially when applied to human clinical data. In humans, peanut allergy IgE is already established as a memory system by the time the allergic individuals are examined by a doctor. In that case, manipulation of the Tfr or IL-10 system the way the authors envisaged could be detrimental rather than beneficial. </div>
<div style="text-align: justify;">
<br /></div>
<div style="text-align: justify;">
posted by David Usharauli </div>
<div style="text-align: justify;">
<br /></div>
<div style="text-align: justify;">
<br /></div>
David Usharaulihttp://www.blogger.com/profile/02668672470276307921noreply@blogger.com4tag:blogger.com,1999:blog-6821948329541212415.post-14840905293593140152020-01-28T19:11:00.000-05:002020-01-28T19:11:27.701-05:00Microbiota-derived peptide and autoimmune heart inflammation: a tale of missing data <div style="text-align: justify;">
Papers published in journal Science supposed to undergo thorough high-level vetting process. However, to err is human. Both reviewers and editors are humans and hence they frequently err, for the annoyance of scientists and for the joy of postdocs doing journal clubs. </div>
<div style="text-align: justify;">
<br /></div>
<div style="text-align: justify;">
Here is an example of a <a href="https://science.sciencemag.org/content/366/6467/881" target="_blank">paper</a> that squeezed through the cracks of the Science vetting process. It claims that peptides derived from certain commensal microbiota species cross-react with heart muscle protein, MYH6, causing autoimmune heart inflammation. It has a great Figure 1 showing that MYH6-specific TCR transgenic mice on a germ-free background, lacking microbiota, is protected from heart autoimmunity.<br />
<br />
<div class="separator" style="clear: both; text-align: center;">
<a href="https://1.bp.blogspot.com/-5n8CLgW_o_Q/XjDLolJbm2I/AAAAAAAAEYc/UURM24bT9tgs_B66b7-dHojfe67mwUuPgCEwYBhgL/s1600/Screenshot%2B%25281891%2529.png" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="761" data-original-width="918" height="265" src="https://1.bp.blogspot.com/-5n8CLgW_o_Q/XjDLolJbm2I/AAAAAAAAEYc/UURM24bT9tgs_B66b7-dHojfe67mwUuPgCEwYBhgL/s320/Screenshot%2B%25281891%2529.png" width="320" /></a></div>
</div>
<div style="text-align: justify;">
<br /></div>
<div style="text-align: justify;">
Furthermore, they showed that the re-introduction of microbiota into germ-free makes these mice susceptible to heart inflammation similar to microbiota+ mice.<br />
<br />
<div class="separator" style="clear: both; text-align: center;">
</div>
<br />
<div class="separator" style="clear: both; text-align: center;">
</div>
<br />
<div class="separator" style="clear: both; text-align: center;">
<a href="https://1.bp.blogspot.com/-LdrPrxQq-9U/XjDL_BUks7I/AAAAAAAAEY4/F4aUqgzwROsQyy7E4enlL59skIBpxSD7ACLcBGAsYHQ/s1600/Screenshot%2B%25281892%2529.png" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="731" data-original-width="1600" height="291" src="https://1.bp.blogspot.com/-LdrPrxQq-9U/XjDL_BUks7I/AAAAAAAAEY4/F4aUqgzwROsQyy7E4enlL59skIBpxSD7ACLcBGAsYHQ/s640/Screenshot%2B%25281892%2529.png" width="640" /></a></div>
</div>
<div style="text-align: justify;">
<br /></div>
<div style="text-align: justify;">
The authors then tried to identify the microbiota species that contribute to this inflammatory condition. An in silico search identified cross-reactive β-galactosidase (β-gal) mimic peptides in <i>Bacteroides thetaiotaomicron</i> (B. theta) and B. faecis with high similarity to MYH6.<br />
<br />
<div class="separator" style="clear: both; text-align: center;">
<a href="https://1.bp.blogspot.com/-3c3a6M9N13k/XjDL_NT7wsI/AAAAAAAAEY0/xRTctsTVqowBu1WUsZ052jo3F74adk-4wCEwYBhgL/s1600/Screenshot%2B%25281893%2529.png" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="537" data-original-width="1107" height="193" src="https://1.bp.blogspot.com/-3c3a6M9N13k/XjDL_NT7wsI/AAAAAAAAEY0/xRTctsTVqowBu1WUsZ052jo3F74adk-4wCEwYBhgL/s400/Screenshot%2B%25281893%2529.png" width="400" /></a></div>
<br />
<br />
The authors even introduced into germ-free TCR transgenic mice <i>Bacteroides thetaiotaomicron</i> (B. theta) lacking the β-gal. Up to now, it feels that the authors have checked all the boxes necessary for high-quality research. But then for some reason, they do not show survival data comparing <i>Bacteroides thetaiotaomicron</i> (B. theta) with and without the β-gal gene as in figure 1. They just showed how a lack of β-gal <i>Bacteroides thetaiotaomicron </i>modifies MYH6-T cells accumulation in the heart tissue.</div>
<div style="text-align: justify;">
<br />
<div class="separator" style="clear: both; text-align: center;">
<a href="https://1.bp.blogspot.com/-VLne-HUmboM/XjDL_MddCsI/AAAAAAAAEZM/odtzxLsYYnsrUkr3VXeuYhXczXo9hWZawCEwYBhgL/s1600/Screenshot%2B%25281894%2529.png" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="676" data-original-width="1184" height="227" src="https://1.bp.blogspot.com/-VLne-HUmboM/XjDL_MddCsI/AAAAAAAAEZM/odtzxLsYYnsrUkr3VXeuYhXczXo9hWZawCEwYBhgL/s400/Screenshot%2B%25281894%2529.png" width="400" /></a></div>
<br />
<br />
So, why the authors don't show survival data of germ-free MYH6 TCR transgenic mice colonized with <i>Bacteroides thetaiotaomicron </i>-/+ β-gal gene? Isn't it the most important result for their hypothesis? Where were reviewers and editors looking?<br />
<br />
posted by David Usharauli<br />
<br />
<br /></div>
David Usharaulihttp://www.blogger.com/profile/02668672470276307921noreply@blogger.com0tag:blogger.com,1999:blog-6821948329541212415.post-11317555866615848872019-11-30T18:28:00.000-05:002019-11-30T18:28:32.568-05:00Tracking deletion of autoreactive clones versus Treg generation for thymically expressed epitopes <div style="text-align: justify;">
So far 3 different outcomes have been identified for developing T cells in the thymus: to develop into naive T cells, get deleted or become Foxp3+ Treg. Both deletion and Treg path require the presence of specific epitopes. However, how a given T cell decides between these pathways is not well understood. </div>
<div style="text-align: justify;">
<br /></div>
<div style="text-align: justify;">
Here is a new paper in <a href="https://www.pnas.org/content/116/37/18537" target="_blank">PNAS </a>that tries to tackle this question using the tetramer tracking approach. The authors are using PLP (brain-specific protein) as an endogenous antigen expressed in the thymus. Surprisingly both PLP<sup>WT</sup> and PLP<sup>KO</sup> mice showed near similar numbers of tetramer-positive T cells in peripheral tissue. However, as expected, only PLP<sup>WT</sup> mice that express PLP epitopes in the thymus but not PLP<sup>KO</sup> mice that do not express the same epitopes showed Treg development.<br />
<br />
</div>
<div class="separator" style="clear: both; text-align: center;">
<a href="https://1.bp.blogspot.com/-vhYVmMX3BW8/XeLiM4IGk_I/AAAAAAAAEXg/9CSUZlZKATMMXWiUHjNc--VTFc6rKDmoQCEwYBhgL/s1600/Screenshot%2B%25281878%2529.png" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="802" data-original-width="1600" height="320" src="https://1.bp.blogspot.com/-vhYVmMX3BW8/XeLiM4IGk_I/AAAAAAAAEXg/9CSUZlZKATMMXWiUHjNc--VTFc6rKDmoQCEwYBhgL/s640/Screenshot%2B%25281878%2529.png" width="640" /></a></div>
<br />
<br />
<br />
Similar results were obtained when thymus tissue was analyzed.<br />
<br />
<br />
<div class="separator" style="clear: both; text-align: center;">
</div>
<div class="separator" style="clear: both; text-align: center;">
<a href="https://1.bp.blogspot.com/-8QDWS02YM4c/XeLiM5HT_WI/AAAAAAAAEXo/tEfLxImMSQYPll7bwJW5Br2utq0qIVJIACEwYBhgL/s1600/Screenshot%2B%25281879%2529.png" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="766" data-original-width="1600" height="304" src="https://1.bp.blogspot.com/-8QDWS02YM4c/XeLiM5HT_WI/AAAAAAAAEXo/tEfLxImMSQYPll7bwJW5Br2utq0qIVJIACEwYBhgL/s640/Screenshot%2B%25281879%2529.png" width="640" /></a> </div>
<div class="separator" style="clear: both; text-align: left;">
<br /></div>
<div class="separator" style="clear: both; text-align: left;">
To make tetramer tracking for reliable the authors used transgenic mice expressing a fixed TCR beta chain. These mice also showed a similar phenotype. </div>
<div class="separator" style="clear: both; text-align: left;">
<br /></div>
<div class="separator" style="clear: both; text-align: center;">
<a href="https://1.bp.blogspot.com/-uoCZWLUmXFg/XeLiMzkXjwI/AAAAAAAAEXc/lgVDv5iEIyAUlBq_8fsMRoR9F4sfE3sjwCEwYBhgL/s1600/Screenshot%2B%25281880%2529.png" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="681" data-original-width="1517" height="286" src="https://1.bp.blogspot.com/-uoCZWLUmXFg/XeLiMzkXjwI/AAAAAAAAEXc/lgVDv5iEIyAUlBq_8fsMRoR9F4sfE3sjwCEwYBhgL/s640/Screenshot%2B%25281880%2529.png" width="640" /></a></div>
<div class="separator" style="clear: both; text-align: left;">
<br /></div>
<div class="separator" style="clear: both; text-align: justify;">
As in PLP<sup>WT</sup> and PLP<sup>KO</sup> mice, fixed:TCR beta mice on PLP<sup>WT</sup> but not on PLP<sup>KO</sup> background harbored Tregs in the periphery. Notable, the rest of the tetramer-positive Foxp3-negative T cells displayed an anergic phenotype (CD73<sup>Hi</sup>FR4<sup>Hi</sup>).</div>
<div class="separator" style="clear: both; text-align: left;">
<br /></div>
<div class="separator" style="clear: both; text-align: left;">
<br /></div>
<div class="separator" style="clear: both; text-align: left;">
<br /></div>
<div class="separator" style="clear: both; text-align: center;">
<a href="https://1.bp.blogspot.com/-nMOaWZIV05w/XeLiNVOrcMI/AAAAAAAAEXo/ysqkYlMmB_QFBjx9_hcuBn0kqJOl1EB3gCEwYBhgL/s1600/Screenshot%2B%25281881%2529.png" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="1147" data-original-width="1485" height="494" src="https://1.bp.blogspot.com/-nMOaWZIV05w/XeLiNVOrcMI/AAAAAAAAEXo/ysqkYlMmB_QFBjx9_hcuBn0kqJOl1EB3gCEwYBhgL/s640/Screenshot%2B%25281881%2529.png" width="640" /></a></div>
<div class="separator" style="clear: both; text-align: left;">
<br /></div>
<div class="separator" style="clear: both; text-align: justify;">
A similar phenotype was found in the thymus. Note, there was an unexpected and significant reduction of tetramer-positive T cells from the thymus to the periphery in fixed:TCR beta mice on PLP<sup>KO</sup> background compared to fixed:TCR beta mice on PLP<sup>WT </sup>background. </div>
<div class="separator" style="clear: both; text-align: left;">
<br /></div>
<div class="separator" style="clear: both; text-align: left;">
<br /></div>
<div class="separator" style="clear: both; text-align: center;">
<a href="https://1.bp.blogspot.com/-ldbt--yWr9s/XeLiNWTI1jI/AAAAAAAAEXo/qXEArm30ougmDbLy1ZADLepr5-aYoKAPACEwYBhgL/s1600/Screenshot%2B%25281882%2529.png" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="1229" data-original-width="1495" height="526" src="https://1.bp.blogspot.com/-ldbt--yWr9s/XeLiNWTI1jI/AAAAAAAAEXo/qXEArm30ougmDbLy1ZADLepr5-aYoKAPACEwYBhgL/s640/Screenshot%2B%25281882%2529.png" width="640" /></a></div>
<div class="separator" style="clear: both; text-align: left;">
<br /></div>
<div class="separator" style="clear: both; text-align: justify;">
So far these data indicated that there is almost no deletion of PLP specific T cells in the thymus on WT mice [compaed KO] but ~2-fold reduction in fixed:TCR beta mice on PLP<sup>WT</sup> compared to KO. Almost half of the tetramer-positive T cells ended up in the Treg pool on the WT background. The remaining T cells showed an anergic phenotype. However the dramatic reduction of tetramer-positive T cells from the thymus to the periphery in KO mice raises some serious unanswered questions.</div>
<div class="separator" style="clear: both; text-align: justify;">
<br /></div>
<div class="separator" style="clear: both; text-align: justify;">
Finally, to find some correlation between TCR specificity and Treg/anergy/deletion phenotype, the authors selected 4 PLP-specific TCRs (denoted here as A, B, C, D). Their analysis showed that some (clone "A") but not other PLP-specific TCRs (clone "C") were able to generate Tregs in the thymus. Notable, TCR "C" displayed the highest affinity to PLP epitope. Also, there is a substantial reduction of clone "C" from the thymus to the periphery in the Foxp3-negative compartment. This possibly reflects the fact that most clones in "C" are anergic and slowly disappear from the periphery. </div>
<div class="separator" style="clear: both; text-align: left;">
<br /></div>
<div class="separator" style="clear: both; text-align: left;">
<br /></div>
<div class="separator" style="clear: both; text-align: center;">
<a href="https://1.bp.blogspot.com/-JJTyLG8uaqk/XeLiOFwGqwI/AAAAAAAAEXk/PUG6RBq2As89-V1CMve5dviJ_h3e-ajcQCEwYBhgL/s1600/Screenshot%2B%25281883%2529.png" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="1129" data-original-width="1600" height="450" src="https://1.bp.blogspot.com/-JJTyLG8uaqk/XeLiOFwGqwI/AAAAAAAAEXk/PUG6RBq2As89-V1CMve5dviJ_h3e-ajcQCEwYBhgL/s640/Screenshot%2B%25281883%2529.png" width="640" /></a></div>
<div class="separator" style="clear: both; text-align: left;">
<br /></div>
<div class="separator" style="clear: both; text-align: left;">
<br /></div>
<div class="separator" style="clear: both; text-align: left;">
<br /></div>
<div class="separator" style="clear: both; text-align: justify;">
In summary, this study re-confirms that tolerance to self-antigens is mostly controlled via Treg generation and that not all antigens/epitopes and their corresponding TCRs are able to participate in this process. There are few unexplained observations in this paper though as discussed above. </div>
<div class="separator" style="clear: both; text-align: justify;">
<br /></div>
<div class="separator" style="clear: both; text-align: justify;">
posted by David Usharauli</div>
<div class="separator" style="clear: both; text-align: left;">
<br /></div>
<div class="separator" style="clear: both; text-align: left;">
<br /></div>
<div class="separator" style="clear: both; text-align: left;">
<br /></div>
<div class="separator" style="clear: both; text-align: left;">
<br /></div>
David Usharaulihttp://www.blogger.com/profile/02668672470276307921noreply@blogger.com0tag:blogger.com,1999:blog-6821948329541212415.post-21669292370252111712019-10-26T18:09:00.000-04:002019-10-26T18:09:14.733-04:00Tumor elimination requires simultaneous expression of both class I and II neo-epitopes <div style="text-align: justify;">
The most tumors express mutant epitopes that could be detected by T cells. According to current paradigm, CD4+ T cells provides help to CD8+ T cells that in turn attack tumors. As tumor cells ordinarily express class I recognized by CD8+ T cells but not class II molecules recognized by CD4+ T cells, primary focus on CD8+ T cell epitopes made a lot of sense. But what about CD4+ T cell 'help' to CD8 T cells? </div>
<div style="text-align: justify;">
<br /></div>
<div style="text-align: justify;">
Indeed, a <a href="https://www.nature.com/articles/s41586-019-1671-8" target="_blank">new</a> 'classically-done' immunology study from Robert Schreiber's lab clearly showed that irrespective class II expression, tumor cells must express both CD8+ and CD4+ T cell neo-epitopes to achieve efficient local tumor control following immunotherapy.</div>
<div style="text-align: justify;">
<br /></div>
<div style="text-align: justify;">
As a starting point, they used nonimmunogenic oncogene-driven KP9025 sarcoma cells (KP), which lack mutational neoantigens. Next they re-expressed in KP cells 2 mutant epitopes, one for class I, mLAMA4, and another for class II, mITGB1 (identified using a hidden Markov model (HMM)-based MHC binding predictor the authors claim is better than other available algorithms). </div>
<div style="text-align: justify;">
<br /></div>
<div class="separator" style="clear: both; text-align: center;">
<a href="https://1.bp.blogspot.com/-1yT5clX4qIc/XbSwYPC9GrI/AAAAAAAAEWY/9WJKn66yhnMkL7EEUeZOD4SkOZ1uppCKQCEwYBhgL/s1600/Screenshot%2B%25281869%2529.png" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="1087" data-original-width="1070" height="400" src="https://1.bp.blogspot.com/-1yT5clX4qIc/XbSwYPC9GrI/AAAAAAAAEWY/9WJKn66yhnMkL7EEUeZOD4SkOZ1uppCKQCEwYBhgL/s400/Screenshot%2B%25281869%2529.png" width="392" /></a></div>
<div style="text-align: justify;">
</div>
<div style="text-align: justify;">
<br /></div>
<div style="text-align: justify;">
A mutant but not wild-type version of ITGB1 was detected by CD4+ TILs.</div>
<div style="text-align: justify;">
<br /></div>
<div class="separator" style="clear: both; text-align: center;">
<a href="https://1.bp.blogspot.com/-RDdV-CgDnEM/XbSwYDKUP0I/AAAAAAAAEWc/41nbBlV2jgIOHkpEUUxyNT8-eNY-LSf6ACEwYBhgL/s1600/Screenshot%2B%25281870%2529.png" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="852" data-original-width="997" height="273" src="https://1.bp.blogspot.com/-RDdV-CgDnEM/XbSwYDKUP0I/AAAAAAAAEWc/41nbBlV2jgIOHkpEUUxyNT8-eNY-LSf6ACEwYBhgL/s320/Screenshot%2B%25281870%2529.png" width="320" /></a></div>
<div style="text-align: justify;">
</div>
<div style="text-align: justify;">
Next, the authors showed that only KP tumors expressing both neo-epitopes but not single expressors, could be eliminated by T cells following immunotherapy. </div>
<div style="text-align: justify;">
<br /></div>
<div style="text-align: justify;">
<br /></div>
<div class="separator" style="clear: both; text-align: center;">
<a href="https://1.bp.blogspot.com/-kgeLlyoXES4/XbSwYAFIZKI/AAAAAAAAEWY/Aqm_7awXwyESf8tkT1pIEqakyzHkMLg9wCEwYBhgL/s1600/Screenshot%2B%25281871%2529.png" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="654" data-original-width="1600" height="260" src="https://1.bp.blogspot.com/-kgeLlyoXES4/XbSwYAFIZKI/AAAAAAAAEWY/Aqm_7awXwyESf8tkT1pIEqakyzHkMLg9wCEwYBhgL/s640/Screenshot%2B%25281871%2529.png" width="640" /></a></div>
<div style="text-align: justify;">
</div>
<div style="text-align: justify;">
As expected, presence of CD4+ T cell epitope enhanced CD8+ T cell response.</div>
<div style="text-align: justify;">
<br /></div>
<div style="text-align: justify;">
<br /></div>
<div class="separator" style="clear: both; text-align: center;">
<a href="https://1.bp.blogspot.com/-q4L5MX2T3_k/XbSwYrrWTUI/AAAAAAAAEWY/-5UyfosKKjkns1UkuawtACDlCIShGlMNwCEwYBhgL/s1600/Screenshot%2B%25281872%2529.png" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="449" data-original-width="1600" height="178" src="https://1.bp.blogspot.com/-q4L5MX2T3_k/XbSwYrrWTUI/AAAAAAAAEWY/-5UyfosKKjkns1UkuawtACDlCIShGlMNwCEwYBhgL/s640/Screenshot%2B%25281872%2529.png" width="640" /></a></div>
<div style="text-align: justify;">
<br /></div>
<div style="text-align: justify;">
Interestingly, both class I and II neo-epitopes must be expressed by the same tumor to mediate protection when used as immunized agents (mixing of single expressor tumors was not enough).</div>
<div style="text-align: justify;">
<br /></div>
<div style="text-align: justify;">
<br /></div>
<div class="separator" style="clear: both; text-align: center;">
<a href="https://1.bp.blogspot.com/-iczHKCFmGuQ/XbSwYzjNUsI/AAAAAAAAEWU/jzZjDY6kDwEVqcnlOcZglrRchtPubrb_ACEwYBhgL/s1600/Screenshot%2B%25281873%2529.png" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="398" data-original-width="1600" height="158" src="https://1.bp.blogspot.com/-iczHKCFmGuQ/XbSwYzjNUsI/AAAAAAAAEWU/jzZjDY6kDwEVqcnlOcZglrRchtPubrb_ACEwYBhgL/s640/Screenshot%2B%25281873%2529.png" width="640" /></a></div>
<div style="text-align: justify;">
<br /></div>
<div style="text-align: justify;">
And notably, expression of both class I and II neo-epitopes were necessary to mediate efficient local tumor control (single expressor tumors were resistant against CD8+ or CD4+ T cells)</div>
<div style="text-align: justify;">
<br /></div>
<div style="text-align: justify;">
<br /></div>
<div class="separator" style="clear: both; text-align: center;">
<a href="https://1.bp.blogspot.com/-oKddiYcg6Kc/XbSwZIMOuEI/AAAAAAAAEWc/IehZ81dLasM9XtGamtxbYRUiDimNSGU3wCEwYBhgL/s1600/Screenshot%2B%25281874%2529.png" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="403" data-original-width="1600" height="160" src="https://1.bp.blogspot.com/-oKddiYcg6Kc/XbSwZIMOuEI/AAAAAAAAEWc/IehZ81dLasM9XtGamtxbYRUiDimNSGU3wCEwYBhgL/s640/Screenshot%2B%25281874%2529.png" width="640" /></a></div>
<div style="text-align: justify;">
<br /></div>
<div style="text-align: justify;">
<br /></div>
<div style="text-align: justify;">
In summary, this is a simple, easy to follow experments that indicate the authors' thought process. It shows that CD4+ T cells 'help' to CD8+ T cells are required both at priming and as well as at effector stage. It is not clear if it is simply a quantitative or rather qualitative issue. It is not known either whether CD4+ T cells do something directly against tumor beyond simply helping CD8+ T cells here. </div>
<div style="text-align: justify;">
<br /></div>
<div style="text-align: justify;">
posted by David Usharauli</div>
<div style="text-align: justify;">
<br /></div>
<div style="text-align: justify;">
<br /></div>
David Usharaulihttp://www.blogger.com/profile/02668672470276307921noreply@blogger.com0tag:blogger.com,1999:blog-6821948329541212415.post-84513225548830473252019-08-27T16:45:00.002-04:002019-08-27T16:45:57.109-04:00The auto-reactive CD4+ T cells provide IL-2 to proto-Tregs in the thymusThe T cells expressing the transcription factor Foxp3 called regulatory T cells, abbreviated as Tregs, are the most important cell type in the immune system. Without them, the whole immune system goes haywire. As a result, the body simply dies in a very short time.<br />
<br />
The Tregs develop in the thymus and require two things: TCR signaling and IL-2. The thymus expresses a very diverse set of epitopes including that from peripheral tissues such as the pancreas or prostate. The high-affinity interaction between TCR and epitope/MHC II makes proto-Treg sensitive to local IL-2, a necessary step to complete a Treg formation loop.<br />
<br />
But what cell provides that crucial IL-2 to proto-Tregs? There hasn't been any consensus with this regard but <a href="http://jem.rupress.org/content/early/2019/08/20/jem.20190993" target="_blank">a new paper</a> in the Journal of Experimental Medicine from Sasha Rudensky's lab indicates that it is mature CD4+ T cells and CD25+Foxp3- CD4+ single-positive (SP) T cells that are the main source of thymic IL-2 required for Treg development.<br />
<br />
For this study, they used an IL-2 reporter mouse wherein cells expressing or having a history of the expression of IL-2 are genetically labeled and analyzed. They found that IL-2 expression was restricted to TCRbeta expressing CD4+ population.<br />
<br />
<br />
<div class="separator" style="clear: both; text-align: center;">
<a href="https://1.bp.blogspot.com/-W2kMKjyjUoo/XWWQ4qOtKEI/AAAAAAAAEU4/oIZzM6hy6CI-qBZYPEtDBhwKS1jYzQxPQCLcBGAs/s1600/Screenshot%2B%25281861%2529.png" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="657" data-original-width="1017" height="257" src="https://1.bp.blogspot.com/-W2kMKjyjUoo/XWWQ4qOtKEI/AAAAAAAAEU4/oIZzM6hy6CI-qBZYPEtDBhwKS1jYzQxPQCLcBGAs/s400/Screenshot%2B%25281861%2529.png" width="400" /></a></div>
<div style="background: transparent; color: #1c1e29; margin-bottom: 0pt; margin-top: 0pt; white-space: pre-wrap; white-space: pre;">
<br /></div>
<br />
Out of CD4+ T cells, the most IL-2 was made by mature CD4 SP and CD25+Foxp3- CD4+ T cell population. Of note, CD25+Foxp3- T cell population contains proto-Tregs.<br />
<br />
<br />
<div class="separator" style="clear: both; text-align: center;">
<a href="https://1.bp.blogspot.com/-ZERZFWImi_8/XWWQ4oyj52I/AAAAAAAAEVA/be2o2R_7a3ABN-CycQvMA4okXEzLoIG2wCEwYBhgL/s1600/Screenshot%2B%25281862%2529.png" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="575" data-original-width="1135" height="202" src="https://1.bp.blogspot.com/-ZERZFWImi_8/XWWQ4oyj52I/AAAAAAAAEVA/be2o2R_7a3ABN-CycQvMA4okXEzLoIG2wCEwYBhgL/s400/Screenshot%2B%25281862%2529.png" width="400" /></a></div>
<div style="background: transparent; color: #1c1e29; margin-bottom: 0pt; margin-top: 0pt; white-space: pre-wrap; white-space: pre;">
<br /></div>
<br />
<br />
Interestingly, the authors also detected mature Tregs with the history of IL-2 expression. It implies that bifurcation between Tregs versus IL-2 producer is a stochastic process.<br />
<br />
<br />
<div class="separator" style="clear: both; text-align: center;">
<a href="https://1.bp.blogspot.com/-PYIspcortsI/XWWRWn7VDZI/AAAAAAAAEVU/VHj_DnZYLIo47lVwgF8bDp7fpWq3XraKQCLcBGAs/s1600/Screenshot%2B%25281865%2529.png" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="517" data-original-width="1114" height="296" src="https://1.bp.blogspot.com/-PYIspcortsI/XWWRWn7VDZI/AAAAAAAAEVU/VHj_DnZYLIo47lVwgF8bDp7fpWq3XraKQCLcBGAs/s640/Screenshot%2B%25281865%2529.png" width="640" /></a></div>
<div style="background: transparent; color: #1c1e29; margin-bottom: 0pt; margin-top: 0pt; white-space: pre-wrap; white-space: pre;">
<br /></div>
<br />
<br />
As expected, TCR signaling together with IL-2 was essential for Treg formation. A "bystander" effect on Foxp3 upregulation on antigen-independent proto-Tregs (Vbeta 8- T cells) could be explained by the fact that these T cells were likely TCR activated in vivo before harvesting for ex vivo experimentation.<br />
<br />
<br />
<div class="separator" style="clear: both; text-align: center;">
<a href="https://1.bp.blogspot.com/-wg-1rd6NJ4g/XWWQ4g-Ye2I/AAAAAAAAEVI/I0xP7wrSHYMOMTQqqWwJV7iHpzo0EEbEACEwYBhgL/s1600/Screenshot%2B%25281863%2529.png" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="626" data-original-width="832" height="300" src="https://1.bp.blogspot.com/-wg-1rd6NJ4g/XWWQ4g-Ye2I/AAAAAAAAEVI/I0xP7wrSHYMOMTQqqWwJV7iHpzo0EEbEACEwYBhgL/s400/Screenshot%2B%25281863%2529.png" width="400" /></a></div>
<br />
Based on these data, the authors suggested the following model: among mature SP CD4 T cells, a small pool produces IL-2 that in the context of high-affinity TCR/epitope interaction and CD25 upregulation promotes Foxp3+ Treg formation either autocrine or paracrine manner. Since the thymus is expressing self epitopes we can conclude that those IL-2 producing T cells are auto-reactive T cells.<br />
<br />
<br />
<div class="separator" style="clear: both; text-align: center;">
<a href="https://1.bp.blogspot.com/-tajZIZl_R3E/XWWQ5P6eK4I/AAAAAAAAEVM/NgSBnKYIMV4iqIkIP-JspWAfTdT0AdEiACEwYBhgL/s1600/Screenshot%2B%25281864%2529.png" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="915" data-original-width="1600" height="366" src="https://1.bp.blogspot.com/-tajZIZl_R3E/XWWQ5P6eK4I/AAAAAAAAEVM/NgSBnKYIMV4iqIkIP-JspWAfTdT0AdEiACEwYBhgL/s640/Screenshot%2B%25281864%2529.png" width="640" /></a></div>
<div style="background: transparent; color: #1c1e29; margin-bottom: 0pt; margin-top: 0pt; white-space: pre-wrap; white-space: pre;">
<br /></div>
The following questions remain unanswered:<br />
<br />
1. What determines Treg, IL-2-producer or deletion pathways? All three options are open for high-affinity TCR+ CD4 SP cells.<br />
<br />
2. Do TCR specificity overlaps between Tregs and IL-2 producers?<br />
<br />
3. What cells provide IL-2 to Tregs in the periphery? <br />
<br />
4. Is IL-2 delivery TCR/epitope-specific or non-specific event?<br />
<br />
<br />
We have recently published a new model, called SPIRAL, that provides answers to these questions. The SPIRAL is based on the principle of epitope cross-reactivity.<br />
<br />
<br />
<a href="https://doi.org/10.7287/peerj.preprints.27853v1"><span class="self-citation-title">Shared TCR epitope cross-reactivity could permit dyads of Foxp3+ regulatory and IL-2-producing T cell precursors to escape thymic purge</span></a> <br />
<br />
<br />
posted by David Usharauli<br />
<br />
<br />
David Usharaulihttp://www.blogger.com/profile/02668672470276307921noreply@blogger.com1tag:blogger.com,1999:blog-6821948329541212415.post-36890436461000112362019-08-13T18:23:00.000-04:002019-08-13T18:54:01.215-04:00Do regulatory CD8+ T cells control autoreactive CD4+ T cells in the mouse model of human MS? <div style="text-align: justify;">
Recently journal Nature published a very thought-provoking study from Mark Davis' lab. <a href="https://www.nature.com/articles/s41586-019-1467-x" target="_blank">In it</a>, the authors have described the existence of a specialized population of CD8+ T cells that prevented auto-reactive CD4+ T cells from causing autoimmune brain inflammation (EAE) in mice, a laboratory model for human multiple sclerosis.<br />
<br />
Let's analyze what the study shows. Both Fig. 1 and Fig. 2 are rather superfluous as they simply show either time kinetics of CD4+, CD8+ and γδ+ T cells responses in the blood or CNS following autoantigen immunization (Fig. 1) or frequency of TCR clonal distribution based on TCR β or both γ and δ sequencing (Fig. 2). It is not clear what was the purpose of showing them within the paper itself.</div>
<div style="text-align: justify;">
</div>
<div class="separator" style="clear: both; text-align: center;">
<a href="https://1.bp.blogspot.com/-Z0YnsLD7zAg/XVM23qTjoOI/AAAAAAAAEUQ/4BMVPv1nxb0Wb33nJs1iEi5TUk_m1VfOACLcBGAs/s1600/Screenshot%2B%25281856%2529.png" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="1001" data-original-width="1600" height="400" src="https://1.bp.blogspot.com/-Z0YnsLD7zAg/XVM23qTjoOI/AAAAAAAAEUQ/4BMVPv1nxb0Wb33nJs1iEi5TUk_m1VfOACLcBGAs/s640/Screenshot%2B%25281856%2529.png" width="640" /></a></div>
<div style="text-align: justify;">
</div>
<div style="text-align: justify;">
</div>
<div style="text-align: justify;">
</div>
<div style="text-align: justify;">
</div>
<div style="text-align: justify;">
<br />
Next, the authors tested the TCR specificities for expanded clones of CD4+ or CD8+ T cells. Four of these CD4+ TCRs expressed in human leukemia SKW αβ−/− cells yielded robust staining with a MOG35–55 I-Ab peptide–MHC tetramer. </div>
<div style="text-align: justify;">
</div>
<div style="text-align: justify;">
Curiously, out of nine TCRs from CD8+ T cell clones expressed in a mouse T cell hybridoma 58 αβ−/− cells, none of them get stimulated when co-cultured with bone-marrow-derived dendritic cells pulsed with myelin protein-derived peptides (total of 350 myelin peptides were tested). So, something else, besides myelin protein, was driving CD8+ T cell expansion.</div>
<div style="text-align: justify;">
</div>
<div class="separator" style="clear: both; text-align: center;">
<a href="https://1.bp.blogspot.com/-ej_L-JpU8lE/XVM23TpErYI/AAAAAAAAEUM/4HMaFzSkJa8sx41moHx50eHror4VfCcaACEwYBhgL/s1600/Screenshot%2B%25281857%2529.png" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="581" data-original-width="1600" height="232" src="https://1.bp.blogspot.com/-ej_L-JpU8lE/XVM23TpErYI/AAAAAAAAEUM/4HMaFzSkJa8sx41moHx50eHror4VfCcaACEwYBhgL/s640/Screenshot%2B%25281857%2529.png" width="640" /></a></div>
<div style="text-align: justify;">
</div>
<div style="text-align: justify;">
<br /></div>
<div style="text-align: justify;">
</div>
<div style="text-align: justify;">
To identify epitope specificity for TCRs from CD8+ T cells, the authors used H2-Db yeast-pMHC libraries. Six of the clonally expanded and one positive control CD8+ TCRs were used. Two, EAE6 and EAE7 TCRs showed robust tetramer staining but no matches were found in the mouse genome. They referred to these peptides identified in the peptide library screen the surrogate peptides (SPs).<br />
<br />
Interestingly, the co-immunization of these SPs with myelin peptide inhibited the development of brain inflammation in mice. </div>
<div style="text-align: justify;">
</div>
<div style="text-align: justify;">
</div>
<div class="separator" style="clear: both; text-align: center;">
<a href="https://1.bp.blogspot.com/-v3_vVxlBYWQ/XVM23QfrjEI/AAAAAAAAEUI/i9ue9LWEb0UCZjNNKJQnb10cPGN-eiDQgCEwYBhgL/s1600/Screenshot%2B%25281858%2529.png" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="518" data-original-width="1600" height="206" src="https://1.bp.blogspot.com/-v3_vVxlBYWQ/XVM23QfrjEI/AAAAAAAAEUI/i9ue9LWEb0UCZjNNKJQnb10cPGN-eiDQgCEwYBhgL/s640/Screenshot%2B%25281858%2529.png" width="640" /></a></div>
<div style="text-align: justify;">
</div>
<div style="text-align: justify;">
</div>
<div style="text-align: justify;">
</div>
<div style="text-align: justify;">
</div>
<div style="text-align: justify;">
</div>
<div style="text-align: justify;">
<br />
More importantly, CD8+ T cells harvested from SPs-immunized mice but not control, naive mice, inhibited myelin-specific but not ovalbumin-specific CD4+ T cells in vitro. </div>
<div style="text-align: justify;">
</div>
<div style="text-align: justify;">
<br />
<div class="separator" style="clear: both; text-align: center;">
<a href="https://1.bp.blogspot.com/-RwiGV9TXUYc/XVM230MdRRI/AAAAAAAAEUU/v64sdy5IxDwOWb6LfgyhSrpc2QyB-O9mQCEwYBhgL/s1600/Screenshot%2B%25281859%2529.png" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="699" data-original-width="1035" height="270" src="https://1.bp.blogspot.com/-RwiGV9TXUYc/XVM230MdRRI/AAAAAAAAEUU/v64sdy5IxDwOWb6LfgyhSrpc2QyB-O9mQCEwYBhgL/s400/Screenshot%2B%25281859%2529.png" width="400" /></a></div>
</div>
<div style="text-align: justify;">
</div>
<div style="text-align: justify;">
</div>
<div style="text-align: justify;">
<br />
Moreover, only Ly49+ but not Ly49− fraction of CD8+CD44+CD122+ T cells from SPs-immunized donor mice showed inhibitory function both in vitro and in vivo. Of note, the application of the anti-Qa-1b antibody had no effect on the CD8 suppression of Myelin-specific CD4+ T cells. Here, the authors also tested CD8+ T cell reactivity to CFA (complete Freund’s adjuvant) or PTX (pertussis toxin) used in EAE immunization protocol and found that it did not increase Ly49+ fraction.</div>
<div style="text-align: justify;">
</div>
<div style="text-align: justify;">
</div>
<div class="separator" style="clear: both; text-align: center;">
<a href="https://1.bp.blogspot.com/-e-6aD0VWhh8/XVM24emP7KI/AAAAAAAAEUk/Iq4VCo_H3JAJdCzhrmi5Z2BLY6WAeziYgCEwYBhgL/s1600/Screenshot%2B%25281860%2529.png" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="551" data-original-width="984" height="223" src="https://1.bp.blogspot.com/-e-6aD0VWhh8/XVM24emP7KI/AAAAAAAAEUk/Iq4VCo_H3JAJdCzhrmi5Z2BLY6WAeziYgCEwYBhgL/s400/Screenshot%2B%25281860%2529.png" width="400" /></a></div>
<div style="text-align: justify;">
<br />
<br />
So, how can we summarize this paper? First, focus on γδ+ T cells here is extra and feels out of context. Second, no endogenous peptides were found that mimic SPs found in the library screen. Could it be microbiota-derived? The authors did not consider this possibility, it appears. Third, how SPs-specific Ly49+ CD8+ T cells inhibit myelin-specific CD4+ T cells? Not clear. It does appear highly specific to myelin-specific CD4+ T cells in the context of brain inflammation. But myelin-specific CD4+ T cells see myelin peptides but these CD8+ T cells do not seem to recognize them. Very confusing indeed. </div>
<div style="text-align: justify;">
</div>
<div style="text-align: justify;">
In general, the "memory-like" CD8+ T cells, such as Qa-1b-restricted population, has been known to inhibit immune response. This paper simply provides some new evidence in that direction. But it is not a novel idea or observation and without some novel mechanistic evidence I don't see how it could have landed in Nature's pages. </div>
<div style="text-align: justify;">
</div>
<div style="text-align: justify;">
</div>
<div style="text-align: justify;">
</div>
<div style="text-align: justify;">
<br />
<br />
posted by David Usharauli <br />
<br />
<br /></div>
David Usharaulihttp://www.blogger.com/profile/02668672470276307921noreply@blogger.com0tag:blogger.com,1999:blog-6821948329541212415.post-249947338185802512019-07-13T19:56:00.001-04:002019-07-13T19:56:38.080-04:00Pathological changes in the gut could initiate autoimmune diabetes microbiota-specific manner<div style="text-align: justify;">
The mouse strain, NOD, has been used to study the mechanism of type 1 diabetes (T1D). These mice spontaneously develop autoimmune diabetes though it is not clear how islet-specific T cells get activated. To track autoimmune T cell fate, TCR transgenic mice, BDC2.5XNOD, have been used. These mice harbor islet-specific TCR expressing T cells in high numbers that are easily monitored.<br />
<br />
A <a href="https://www.pnas.org/content/early/2019/06/05/1814558116" target="_blank">new study</a> in PNAS did some experiments on BDC2.5XNOD mice to understand the initiation of autoimmunity. First, they showed that the NOD background showed increased gut wall barrier permeability by measuring the FITC-dextran level in the blood after oral application (though they did not show the same permeability test for BDC2.5XNOD mice).<br />
<br />
<div class="separator" style="clear: both; text-align: center;">
<a href="https://1.bp.blogspot.com/-puTk77BTf-s/XSpotY1aADI/AAAAAAAAESw/-oq11ATHlGgFF4pYLEZzHP6dNxE-p34CwCLcBGAs/s1600/Capture1.PNG" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="630" data-original-width="966" height="260" src="https://1.bp.blogspot.com/-puTk77BTf-s/XSpotY1aADI/AAAAAAAAESw/-oq11ATHlGgFF4pYLEZzHP6dNxE-p34CwCLcBGAs/s400/Capture1.PNG" width="400" /></a></div>
</div>
<div style="text-align: justify;">
</div>
<div style="text-align: justify;">
<br />
Interestingly, BDC2.5XNOD mice do not develop spontaneous autoimmune diabetes. However, oral application of low-dose dextran-sulfate sodium (DSS) activates T cells and initiates diabetes.<br />
<br />
<div class="separator" style="clear: both; text-align: center;">
<a href="https://1.bp.blogspot.com/-5isO57Y5NV0/XSpotea3OmI/AAAAAAAAES4/h-3vFp83kj0-KOzioc9tl4bU7AJJj9CNQCLcBGAs/s1600/Capture2.PNG" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="523" data-original-width="744" height="224" src="https://1.bp.blogspot.com/-5isO57Y5NV0/XSpotea3OmI/AAAAAAAAES4/h-3vFp83kj0-KOzioc9tl4bU7AJJj9CNQCLcBGAs/s320/Capture2.PNG" width="320" /></a></div>
<br />
<div class="separator" style="clear: both; text-align: center;">
<a href="https://1.bp.blogspot.com/-iV5TWdVLk1o/XSpotWpD0aI/AAAAAAAAES0/Vr10urS_pU4ss1vrOx8ig9rAU2W4KvfngCLcBGAs/s1600/Capture3.PNG" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="455" data-original-width="616" height="236" src="https://1.bp.blogspot.com/-iV5TWdVLk1o/XSpotWpD0aI/AAAAAAAAES0/Vr10urS_pU4ss1vrOx8ig9rAU2W4KvfngCLcBGAs/s320/Capture3.PNG" width="320" /></a></div>
<div class="separator" style="clear: both; text-align: center;">
</div>
</div>
<div style="text-align: justify;">
<br />
<br />
<br />
Diabetes, however, does not develop if DSS-treated BDC2.5XNOD mice are depleted of endogenous microbiota or if naive BDC2.5XNOD mice received DSS-modified microbiota.<br />
<br />
<br />
<div class="separator" style="clear: both; text-align: center;">
<a href="https://1.bp.blogspot.com/-1AQO98ZIELs/XSpotxr_fcI/AAAAAAAAES8/qt-BlqkFdHwEAxqw_baaPQVfY7taeJDnQCLcBGAs/s1600/Capture4.PNG" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="1009" data-original-width="969" height="400" src="https://1.bp.blogspot.com/-1AQO98ZIELs/XSpotxr_fcI/AAAAAAAAES8/qt-BlqkFdHwEAxqw_baaPQVfY7taeJDnQCLcBGAs/s400/Capture4.PNG" width="383" /></a></div>
<br />
<br />
<br />
<div class="separator" style="clear: both; text-align: center;">
</div>
<br />
In summary, this study showed that both gut inflammation and microbiota are necessary for the initiation of autoimmune diabetes in BDC2.5XNOD mice. The most likely scenario is that changes introduced by DSS allow endogenous microbiota to activate islet-specific T cells via cross-reactive antigens. DSS modifies both gut wall permeability and microbiota. Both of these phenomena have been observed by the authors. They conclude that "restoration of a healthy gut barrier through microbiota and diet modulation in diabetes-prone individuals could ultimately reduce intestinal activation of islet-reactive T cells and prevent T1D occurrence".<br />
<br />
Others, in news/views for this article, even suggested using antibiotics to deplete endogenous microbiota, but in my opinion, this is a premature suggestion because the authors did not show that microbiota depletion after diabetes has already developed could stop it.<br />
<br />
posted by David Usharauli<br />
<br />
<br />
<br /></div>
David Usharaulihttp://www.blogger.com/profile/02668672470276307921noreply@blogger.com0tag:blogger.com,1999:blog-6821948329541212415.post-88509511208430828472019-06-29T18:06:00.000-04:002019-06-29T18:19:03.833-04:00Select microbiota species provides protection against food allergy via RORγt+ Tregs<div style="text-align: justify;">
It is now undoubtedly acknowledged that body's microbiota plays a decisive role in protection against allergy, including food allergy. But how exactly microbiota does it is less clear.</div>
<div style="text-align: justify;">
<br /></div>
<div style="text-align: justify;">
A new study in mice published in <a href="https://www.nature.com/articles/s41591-019-0461-z" target="_blank">Nature Medicine</a> suggests the certain microbiota species signal subset of FOXP3+ Tregs called RORγt+ Tregs via adaptor MyD88 to exert its protective role against food allergy.</div>
<div style="text-align: justify;">
<br /></div>
<div style="text-align: justify;">
The most of the experiments reported here were done in genetically modified mice called <i>Il4ra</i><sup>F709</sup> that shows a predisposition to allergy due to an alteration in IL-4 signaling. Here, germ-free <i>Il4ra</i><sup>F709 </sup>mice were colonized with microbiota consortium differently enriched between non-allergic versus allergic infants. Out of those, defined mix of Clostridiales and Bacteriodales but not Proteobacteria could reduce allergic reaction in <i>Il4ra</i><sup>F709 </sup> mice. (Note, you can click the image to expand it to see it more accurately).</div>
<div style="text-align: justify;">
<br /></div>
<div style="text-align: justify;">
<br /></div>
<div style="text-align: justify;">
<br /></div>
<div class="separator" style="clear: both; text-align: center;">
<a href="https://1.bp.blogspot.com/-XLDtuV8mSY4/XRfHenFBd_I/AAAAAAAAER8/1xvuDBvJWZQ6umKH9eqBby6d_KgZMJmbwCEwYBhgL/s1600/Screenshot%2B%25281846%2529.png" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="339" data-original-width="1600" height="135" src="https://1.bp.blogspot.com/-XLDtuV8mSY4/XRfHenFBd_I/AAAAAAAAER8/1xvuDBvJWZQ6umKH9eqBby6d_KgZMJmbwCEwYBhgL/s640/Screenshot%2B%25281846%2529.png" width="640" /></a></div>
<div style="text-align: justify;">
<br />
<br />
<br />
In a separate set of experiments the authors noticed that <i>Il4ra</i><sup>F709 </sup>mice or mice specifically deficient for RORγt+ Tregs subset displayed similar phenotype in response to allergic challenge. They thought there could be a connection.<br />
<br />
<br />
<div class="separator" style="clear: both; text-align: center;">
<a href="https://1.bp.blogspot.com/-uHYDOHld_eA/XRfHevgZ_NI/AAAAAAAAESQ/9EodZWjXfToaUSEtIr5bUDeA0tKhV-aYQCEwYBhgL/s1600/Screenshot%2B%25281847%2529.png" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="695" data-original-width="1600" height="276" src="https://1.bp.blogspot.com/-uHYDOHld_eA/XRfHevgZ_NI/AAAAAAAAESQ/9EodZWjXfToaUSEtIr5bUDeA0tKhV-aYQCEwYBhgL/s640/Screenshot%2B%25281847%2529.png" width="640" /></a></div>
<br />
<br />
Indeed, <i>Il4ra</i><sup>F709 </sup>mice deficient for RORγt+ Tregs subset lost an ability to resist allergic reaction when colonized with defined mix of Clostridiales and Bacteriodales.<br />
<br />
<br />
<br />
<br />
<div class="separator" style="clear: both; text-align: center;">
<a href="https://1.bp.blogspot.com/-pxgq0P6m-og/XRfHeqb4ZYI/AAAAAAAAESQ/DXXSr05z2Roq2mWwnd_YX2trdgW-Gt-TACEwYBhgL/s1600/Screenshot%2B%25281848%2529.png" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="334" data-original-width="1600" height="132" src="https://1.bp.blogspot.com/-pxgq0P6m-og/XRfHeqb4ZYI/AAAAAAAAESQ/DXXSr05z2Roq2mWwnd_YX2trdgW-Gt-TACEwYBhgL/s640/Screenshot%2B%25281848%2529.png" width="640" /></a></div>
<br />
<br />
Finally, the authors attributed the loss of protection to loss of MyD88 adaptor signaling in Tregs because <i>Il4ra</i><sup>F709 </sup>mice deficient for MyD88 signaling in Tregs also showed loss of protection against allergic reaction when colonized with defined mix of Clostridiales and Bacteriodales (Note, oral short chain fatty acid (SCFA) therapy failed to protect <i>Il4ra</i><sup>F709 </sup>mice against allergic response) .<br />
<br />
<br />
<br />
<br />
<div class="separator" style="clear: both; text-align: center;">
<a href="https://1.bp.blogspot.com/-14wBTf73BT8/XRfHfSETHcI/AAAAAAAAESM/TCFhxwArIVwmTxoAWhY1UPzAnG0eZZoWACEwYBhgL/s1600/Screenshot%2B%25281849%2529.png" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="373" data-original-width="1600" height="148" src="https://1.bp.blogspot.com/-14wBTf73BT8/XRfHfSETHcI/AAAAAAAAESM/TCFhxwArIVwmTxoAWhY1UPzAnG0eZZoWACEwYBhgL/s640/Screenshot%2B%25281849%2529.png" width="640" /></a></div>
<br />
<br />
<br />
In summary, we could conclude based on this and other studies that RORγt+ Tregs do play a decisive role in protection against unwanted inflammatory response (Note, however, that allergic sensitization protocol employed here is not exactly "translational" approach).<br />
<br />
One major drawback of this study is that the authors failed to examine why it is that Clostridiales and Bacteriodales but not Proteobacteria or other species could signal via MyD88 to provide protection against allergic response. In my view it is not a difference in innate signaling molecules that distinguishes protective versus non-protective microbiota species but rather their antigenic composition that provides epitopes to RORγt+ Tregs to keep them active and in a good functioning condition (MyD88 could be just necessary to keep such antigen-specific Tregs active due to its role in metabolic pathways).<br />
<br />
posted by David Usharauli<br />
<br />
<br /></div>
David Usharaulihttp://www.blogger.com/profile/02668672470276307921noreply@blogger.com0tag:blogger.com,1999:blog-6821948329541212415.post-78597061292122856942019-06-18T20:25:00.002-04:002019-06-24T15:18:54.845-04:00A neonatal temporal window for thymic epitope-specific Foxp3+ Treg formation<div style="text-align: justify;">
The thymus-derived Foxp3+ Tregs are indisputably the most important immune cell type. Surprisingly, little has been done to found out their antigen specificity. One reason for this lack of interest to study it has to do with the fact most scientists thought Tregs inhibited unwanted T cell responses antigen non-specific manner. So, they reasoned why to bother with TCR specificity. More recently however they started to pay close attention to antigen-specificity of Tregs since it became clear that antigen-specific Tregs showed superior, maybe even exclusive, therapeutic effect in animal models. </div>
<div style="text-align: justify;">
<br /></div>
<div style="text-align: justify;">
So any study that advances our understanding of the formation of antigen-specific Tregs is immensely valuable. Below I will review one such research published in <a href="https://www.nature.com/articles/s41590-019-0414-1" target="_blank">Nature Immunology</a> from Eric Huseby's lab at the University of Massachusetts Medical School, Worcester, MA, USA.</div>
<div style="text-align: justify;">
<br /></div>
<div style="text-align: justify;">
In this study, they cloned several hundred TCRs from Foxp3+ GFP+ Tregs and screened their specificity in an <i>in vitro</i> IL-2 bioassay using standard hybridoma technology and library of ~1,750 unique self-peptides (it is astounding that so few labs have used this readily available approach). About 17 peptides showed a positive response. They chose to focus on 2 peptides derived from peptidyl arginine deiminase type IV (Padi4<sub>92–105</sub>) and Adducin 2 (Add2<sub>606–621</sub>). TCR specificity for Padi4<sub>92–105</sub> or Add2<sub>606–621</sub> was confirmed with respective KO mice.<br />
<br />
<div class="separator" style="clear: both; text-align: center;">
<a href="https://1.bp.blogspot.com/-U9n0vDwCUwI/XQlzYXsYeaI/AAAAAAAAEO4/jefrhH4PpVw7Q2NAzbSum6WLW2eGR-7FQCEwYBhgL/s1600/Screenshot%2B%25281837%2529.png" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="997" data-original-width="1600" height="398" src="https://1.bp.blogspot.com/-U9n0vDwCUwI/XQlzYXsYeaI/AAAAAAAAEO4/jefrhH4PpVw7Q2NAzbSum6WLW2eGR-7FQCEwYBhgL/s640/Screenshot%2B%25281837%2529.png" width="640" /></a></div>
<br />
<br />
<br />
Curiously, they noticed that thymic development of Padi4<sub>92–105 </sub>specific Tregs was time restricted and their formation rapidly went down after 3 weeks post birth.<br />
<br />
<div class="separator" style="clear: both; text-align: center;">
<a href="https://1.bp.blogspot.com/-oBqM4J_gBvY/XQlzYcyk2_I/AAAAAAAAEO8/LtKnewAfovchX0puKBP33M4c5vSr18CnACEwYBhgL/s1600/Screenshot%2B%25281838%2529.png" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="900" data-original-width="1600" height="360" src="https://1.bp.blogspot.com/-oBqM4J_gBvY/XQlzYcyk2_I/AAAAAAAAEO8/LtKnewAfovchX0puKBP33M4c5vSr18CnACEwYBhgL/s640/Screenshot%2B%25281838%2529.png" width="640" /></a></div>
<br />
<br />
<br />
More importantly, specific antigen expression was primarily responsible for both initial Treg formation and later its reduction.<br />
<br />
<div class="separator" style="clear: both; text-align: center;">
<a href="https://1.bp.blogspot.com/-g5HtaxSUFlE/XQlzYYiwabI/AAAAAAAAEPA/_0zw9NQe18wb8nofFdpRui9H31T0rwKnwCEwYBhgL/s1600/Screenshot%2B%25281839%2529.png" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="1071" data-original-width="1600" height="428" src="https://1.bp.blogspot.com/-g5HtaxSUFlE/XQlzYYiwabI/AAAAAAAAEPA/_0zw9NQe18wb8nofFdpRui9H31T0rwKnwCEwYBhgL/s640/Screenshot%2B%25281839%2529.png" width="640" /></a></div>
<br />
<br />
<br />
However, even if there was initially an age-related decline in the frequency of Padi4<sub>92–105 </sub>specific Tregs both in the thymus and periphery, their absolute numbers were maintained at a constant level in the periphery afterward. This is important to highlight.<br />
<br />
<br />
<div class="separator" style="clear: both; text-align: center;">
<a href="https://1.bp.blogspot.com/-bbeI7UjmZeE/XQqSPFyx4II/AAAAAAAAEPU/vMaOKlQELuw9a_GmOEUva6iWDN7ft91LwCLcBGAs/s1600/Screenshot%2B%25281844%2529.png" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="1121" data-original-width="1358" height="528" src="https://1.bp.blogspot.com/-bbeI7UjmZeE/XQqSPFyx4II/AAAAAAAAEPU/vMaOKlQELuw9a_GmOEUva6iWDN7ft91LwCLcBGAs/s640/Screenshot%2B%25281844%2529.png" width="640" /></a></div>
<br />
<br />
<br />
<br />
Notably, this age-related antigen-dependent Treg reduction could be reversed in chimera where only thymic stromal but not bone-marrow derived cells expressed specific epitope. It could mean dose effect or specialized antigen-presentation pathway contributes to age-related decline in Padi4<sub>92–105 </sub>specific Tregs formation.<br />
<br />
<br />
<div class="separator" style="clear: both; text-align: center;">
<a href="https://1.bp.blogspot.com/-fRkRL7Bt_6c/XQlzZALuvFI/AAAAAAAAEPA/JB0OAn_WRbAkwwBMv5ubt0Kf51gqGE3XwCEwYBhgL/s1600/Screenshot%2B%25281841%2529.png" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="938" data-original-width="1326" height="451" src="https://1.bp.blogspot.com/-fRkRL7Bt_6c/XQlzZALuvFI/AAAAAAAAEPA/JB0OAn_WRbAkwwBMv5ubt0Kf51gqGE3XwCEwYBhgL/s640/Screenshot%2B%25281841%2529.png" width="640" /></a></div>
<br />
<br />
Furthermore, out of several Padi4<sub>92–105 </sub>specific TCRs with different antigen response potency, only moderate potency responders were enriched in Tregs in the periphery (the highest potency T cells were lost in the thymus and the lowest potency T cells ended up in Tconv spleen pool). In my view, this is conveniently too clean to my liking.<br />
<br />
<div class="separator" style="clear: both; text-align: center;">
<a href="https://1.bp.blogspot.com/-Sr7WB0lLEcM/XQlzZdDtVgI/AAAAAAAAEO8/DWqmIFrHOokGvg9Sn2QbyZkCzPGCjef1gCEwYBhgL/s1600/Screenshot%2B%25281842%2529.png" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="960" data-original-width="1600" height="382" src="https://1.bp.blogspot.com/-Sr7WB0lLEcM/XQlzZdDtVgI/AAAAAAAAEO8/DWqmIFrHOokGvg9Sn2QbyZkCzPGCjef1gCEwYBhgL/s640/Screenshot%2B%25281842%2529.png" width="640" /></a></div>
<br />
<br />
<br />
Also, the authors found Treg formation best correlated with the TCR:self-MHC half-life (t<sub>1/2</sub>).<br />
<br />
<div class="separator" style="clear: both; text-align: center;">
<a href="https://1.bp.blogspot.com/-rudrwtXtC2s/XQlzZr-6H-I/AAAAAAAAEO8/EFUKumhfn0ARcXaRV6_rjGbW9m-FJY-0ACEwYBhgL/s1600/Screenshot%2B%25281843%2529.png" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="428" data-original-width="1600" height="170" src="https://1.bp.blogspot.com/-rudrwtXtC2s/XQlzZr-6H-I/AAAAAAAAEO8/EFUKumhfn0ARcXaRV6_rjGbW9m-FJY-0ACEwYBhgL/s640/Screenshot%2B%25281843%2529.png" width="640" /></a></div>
<br />
<br />
In summary, this study identified several self epitopes that drive mouse Treg formation in the thymus and this process is restricted to a few weeks post birth. It is not clear why or how the cessation of Treg formation is happening in the thymus here. As absolute numbers of such epitope-specific Tregs that seeded the periphery stayed constant it could indicate that a saturation feedback loop may exist between periphery and thymus that adjust Treg numbers. Additionally, the authors suggest that Treg formation could be predicted based solely on TCR:self-MHC dwell half-life (t<sub>1/2</sub>). However, dwell time cannot explain their own observation about the age-related decline of Treg formation. What has changed in 8-week versus 3-week thymus to upend dwell time so dramatically? Besides, this paper did not address a mechanism of bifurcation that determines deletion versus Treg formation at the single thymocyte level that has been shown to occur independently of TCR affinity. <br />
<br />
Of note, these results could explain why some CD4+ TCR transgenic mice don't show thymic Foxp3+ Treg formation but still harbor them in the periphery, for example, marilyn CD4+ TCR transgenic mouse. As such mice are ordinarily examined when they are adults (>8 weeks) it will miss the thymic phase. <br />
<br />
posted by David Usharauli <br />
<br />
<br />
<br />
<div class="separator" style="clear: both; text-align: center;">
</div>
<div class="separator" style="clear: both; text-align: center;">
</div>
<div class="separator" style="clear: both; text-align: center;">
</div>
<div class="separator" style="clear: both; text-align: center;">
</div>
<div class="separator" style="clear: both; text-align: center;">
</div>
<div class="separator" style="clear: both; text-align: center;">
</div>
<div class="separator" style="clear: both; text-align: center;">
</div>
<div class="separator" style="clear: both; text-align: center;">
</div>
<div class="separator" style="clear: both; text-align: center;">
</div>
</div>
David Usharaulihttp://www.blogger.com/profile/02668672470276307921noreply@blogger.com0tag:blogger.com,1999:blog-6821948329541212415.post-15940398016478566282019-05-25T17:03:00.000-04:002019-05-25T17:03:25.187-04:00Allergy: A newborn's microbiota prevents hyper IgE antibody response to certain food antigens <div style="text-align: justify;">
Prevalence of allergy to food antigens is increasing in the world (alongside autoimmune diseases). Many believe it has to do with changes in microbiota composition due to environmental and processed food effects. But we still don't know how exactly microbiota prevents immune dysregulation characteristic of allergy or autoimmunity. </div>
<div style="text-align: justify;">
<br /></div>
<div style="text-align: justify;">
For the past couple of years the team from South Korea has published several important papers addressing the role of microbiota and food antigens in modifying the gut immune system. This week they published yet another relevant paper in <a href="https://advances.sciencemag.org/content/5/5/eaaw1507" target="_blank">Science Advance</a>. Below I present the highlights of the study. </div>
<div style="text-align: justify;">
<br /></div>
<div style="text-align: justify;">
For this study the authors compared the level of IgE in sera from conventional mice fed regular diet, germ-free mice also fed regular sterile diet and germ-free mice fed with sterile antigen-free diet. As seen in the figure below GF mice develop, over time, hyper IgE condition. However, this effect was abolished in GF mice fed antigen-free diet. It indicated that antigens found in food interact with the immune system differently in the absence of microbiota. </div>
<div style="text-align: justify;">
<br /></div>
<div class="separator" style="clear: both; text-align: center;">
<a href="https://1.bp.blogspot.com/-tUQkGDTBXF4/XOmgicgvnoI/AAAAAAAAENY/5HfutRBYxIc59TOJgh5oe3tTPdyh1XWNgCLcBGAs/s1600/Screenshot%2B%25281826%2529.png" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="814" data-original-width="1180" height="275" src="https://1.bp.blogspot.com/-tUQkGDTBXF4/XOmgicgvnoI/AAAAAAAAENY/5HfutRBYxIc59TOJgh5oe3tTPdyh1XWNgCLcBGAs/s400/Screenshot%2B%25281826%2529.png" width="400" /></a></div>
<div style="text-align: justify;">
<br /></div>
<div style="text-align: justify;">
<br /></div>
<div style="text-align: justify;">
This was confirmed in reciprocal experiments where GF mice were introduced to the antigen-free diet or when antigen-free diet fed GF mice were introduced to a regular diet. In both conditions, a regular diet that contains antigens enhanced IgE level in the absence of microbiota.</div>
<div style="text-align: justify;">
<br /></div>
<div class="separator" style="clear: both; text-align: center;">
<a href="https://1.bp.blogspot.com/-4yIfyOnSYQs/XOmgiZpLhtI/AAAAAAAAEN0/Dm18_rv6GgkbIAAqym3l6OSmTrXpTMjKgCEwYBhgL/s1600/Screenshot%2B%25281827%2529.png" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="815" data-original-width="1073" height="303" src="https://1.bp.blogspot.com/-4yIfyOnSYQs/XOmgiZpLhtI/AAAAAAAAEN0/Dm18_rv6GgkbIAAqym3l6OSmTrXpTMjKgCEwYBhgL/s400/Screenshot%2B%25281827%2529.png" width="400" /></a></div>
<div style="text-align: justify;">
<br /></div>
<div style="text-align: justify;">
Interestingly, the authors found that only certain food antigens, such as wheat gluten, could initiate hyper IgE response in absence of microbiota. Of note, the wheat gluten was shown to be digestion resistant. </div>
<div style="text-align: justify;">
<br /></div>
<div style="text-align: justify;">
<br /></div>
<div class="separator" style="clear: both; text-align: center;">
<a href="https://1.bp.blogspot.com/-QHxtGesMXJs/XOmgiXE9_7I/AAAAAAAAEN0/oFfPvO1Jah8vRa11RoUxQ2L9Ffef9XVHgCEwYBhgL/s1600/Screenshot%2B%25281828%2529.png" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="699" data-original-width="1600" height="276" src="https://1.bp.blogspot.com/-QHxtGesMXJs/XOmgiXE9_7I/AAAAAAAAEN0/oFfPvO1Jah8vRa11RoUxQ2L9Ffef9XVHgCEwYBhgL/s640/Screenshot%2B%25281828%2529.png" width="640" /></a></div>
<div style="text-align: justify;">
<br /></div>
<div style="text-align: justify;">
<br /></div>
<div style="text-align: justify;">
<br /></div>
<div style="text-align: justify;">
Another noteworthy observation was related to the age at which point mice were introduced to food antigens. Only young, but not older antigen-free fed mice, showed hyper IgE response when introduced to food antigens in the absence of microbiota. It indicated that there were some differences between young and older mice that made older mice resistant to hyper IgE production when responding to food antigens. </div>
<div style="text-align: justify;">
<br /></div>
<div style="text-align: justify;">
<br /></div>
<div class="separator" style="clear: both; text-align: center;">
<a href="https://1.bp.blogspot.com/-PPm0tg-H5X8/XOmgjKk0spI/AAAAAAAAENw/O9RVZ_ZBKxgwb7_B5ORlzIc7P-DksgN1QCEwYBhgL/s1600/Screenshot%2B%25281830%2529.png" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="1174" data-original-width="1600" height="292" src="https://1.bp.blogspot.com/-PPm0tg-H5X8/XOmgjKk0spI/AAAAAAAAENw/O9RVZ_ZBKxgwb7_B5ORlzIc7P-DksgN1QCEwYBhgL/s400/Screenshot%2B%25281830%2529.png" width="400" /></a></div>
<div style="text-align: justify;">
<br /></div>
<div style="text-align: justify;">
So far we discussed how antigen-free fed mice respond to food antigens in the absence of microbiota. As expected, the introduction of microbiota to GF mice blocked hyper IgE response to food antigens. </div>
<div style="text-align: justify;">
<br /></div>
<div style="text-align: justify;">
<br /></div>
<div class="separator" style="clear: both; text-align: center;">
<a href="https://1.bp.blogspot.com/--ZGfcro-w-g/XOmgjYqoidI/AAAAAAAAEN4/wJHOA5Er65g3xmTEMwbKXbyD6sM8a-GpgCEwYBhgL/s1600/Screenshot%2B%25281831%2529.png" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="864" data-original-width="1190" height="290" src="https://1.bp.blogspot.com/--ZGfcro-w-g/XOmgjYqoidI/AAAAAAAAEN4/wJHOA5Er65g3xmTEMwbKXbyD6sM8a-GpgCEwYBhgL/s400/Screenshot%2B%25281831%2529.png" width="400" /></a></div>
<div style="text-align: justify;">
<br /></div>
<div style="text-align: justify;">
<br /></div>
<div style="text-align: justify;">
In summary, this study showed that in the absence of normal microbiota mice fed a regular diet that contains antigens will show hyper IgE response to certain food antigens. This response is abolished in GF mice fed antigen-free diet. The main question of how microbiota prevents IgE response or why certain food antigens are more immunogenic has not been addressed here. Also, the authors did not discuss it but it is important to mention here that hyper IgE response by itself does not mean pathological allergic response. The authors did not say that antigen-free mice fed regular diet became allergic to it (or to wheat gluten). It means that allergic sensitization requires additional mechanisms beyond hyper IgE response.</div>
<div style="text-align: justify;">
<br /></div>
<div style="text-align: justify;">
posted by David Usharauli </div>
<div style="text-align: justify;">
<br /></div>
<div style="text-align: justify;">
<br /></div>
<div style="text-align: justify;">
<br /></div>
David Usharaulihttp://www.blogger.com/profile/02668672470276307921noreply@blogger.com0tag:blogger.com,1999:blog-6821948329541212415.post-58487690370077240972019-04-23T20:07:00.000-04:002019-04-23T20:09:20.273-04:00CD80 sequesters PDL1 on DC's surface and promotes T cell activation<blockquote class="twitter-tweet tw-align-center" data-lang="en">
<div dir="ltr" lang="en">
An excellent study by Japanese scientists in <a href="https://twitter.com/sciencemagazine?ref_src=twsrc%5Etfw">@sciencemagazine</a> reveals how co-<a href="https://twitter.com/hashtag/stimulatory?src=hash&ref_src=twsrc%5Etfw">#stimulatory</a> molecule <a href="https://twitter.com/hashtag/CD80?src=hash&ref_src=twsrc%5Etfw">#CD80</a> sequestered co-<a href="https://twitter.com/hashtag/inhibitory?src=hash&ref_src=twsrc%5Etfw">#inhibitory</a> molecule <a href="https://twitter.com/hashtag/PDL1?src=hash&ref_src=twsrc%5Etfw">#PDL1</a> on the same DC's surface and thus promotes <a href="https://twitter.com/hashtag/Tcell?src=hash&ref_src=twsrc%5Etfw">#Tcell</a> <a href="https://twitter.com/hashtag/activation?src=hash&ref_src=twsrc%5Etfw">#activation</a>. <a href="https://twitter.com/hashtag/immunology?src=hash&ref_src=twsrc%5Etfw">#immunology</a> <a href="https://twitter.com/hashtag/tolerance?src=hash&ref_src=twsrc%5Etfw">#tolerance</a> <a href="https://twitter.com/hashtag/Immunotherapy?src=hash&ref_src=twsrc%5Etfw">#Immunotherapy</a> <a href="https://t.co/RcArRXV9XT">https://t.co/RcArRXV9XT</a></div>
— David Usharauli (@3DiMMUNE) <a href="https://twitter.com/3DiMMUNE/status/1120839317507772416?ref_src=twsrc%5Etfw">April 23, 2019</a></blockquote>
<script async="" charset="utf-8" src="https://platform.twitter.com/widgets.js"></script>
<br />
<blockquote class="twitter-tweet tw-align-center" data-lang="en">
<div dir="ltr" lang="en">
1. Initially, the authors made an <a href="https://twitter.com/hashtag/observation?src=hash&ref_src=twsrc%5Etfw">#observation</a> that unlike <a href="https://twitter.com/hashtag/macrophages?src=hash&ref_src=twsrc%5Etfw">#macrophages</a> <a href="https://twitter.com/hashtag/dendritic?src=hash&ref_src=twsrc%5Etfw">#dendritic</a> cells did not stain with soluble <a href="https://twitter.com/hashtag/PD1?src=hash&ref_src=twsrc%5Etfw">#PD1</a> molecule even though DCs expressed high levels of <a href="https://twitter.com/hashtag/PDL1?src=hash&ref_src=twsrc%5Etfw">#PDL1</a> or <a href="https://twitter.com/hashtag/PDL2?src=hash&ref_src=twsrc%5Etfw">#PDL2</a> (PD1 ligands). However, it was noted that DCs expressed a higher level of <a href="https://twitter.com/hashtag/CD80?src=hash&ref_src=twsrc%5Etfw">#CD80</a> too. <a href="https://t.co/hH1CbYxt7L">pic.twitter.com/hH1CbYxt7L</a></div>
— David Usharauli (@3DiMMUNE) <a href="https://twitter.com/3DiMMUNE/status/1120839318883446785?ref_src=twsrc%5Etfw">April 23, 2019</a></blockquote>
<script async="" charset="utf-8" src="https://platform.twitter.com/widgets.js"></script>
<br />
<blockquote class="twitter-tweet tw-align-center" data-lang="en">
<div dir="ltr" lang="en">
3. Co-expression of <a href="https://twitter.com/hashtag/PDL1?src=hash&ref_src=twsrc%5Etfw">#PDL1</a> with <a href="https://twitter.com/hashtag/CD80?src=hash&ref_src=twsrc%5Etfw">#CD80</a> [but not with CD86 or PDL2 with CD80 or another co-<a href="https://twitter.com/hashtag/stimulatory?src=hash&ref_src=twsrc%5Etfw">#stimulatory</a> molecule CD86], on the same cell surface had a <a href="https://twitter.com/hashtag/functional?src=hash&ref_src=twsrc%5Etfw">#functional</a> consequence for OVA-specific T cell activation. It allowed more vigorous <a href="https://twitter.com/hashtag/activation?src=hash&ref_src=twsrc%5Etfw">#activation</a> and IL-2 production. <a href="https://t.co/X0miudAspA">pic.twitter.com/X0miudAspA</a></div>
— David Usharauli (@3DiMMUNE) <a href="https://twitter.com/3DiMMUNE/status/1120839322100469760?ref_src=twsrc%5Etfw">April 23, 2019</a></blockquote>
<script async="" charset="utf-8" src="https://platform.twitter.com/widgets.js"></script>
<br />
<blockquote class="twitter-tweet tw-align-center" data-lang="en">
<div dir="ltr" lang="en">
5. Here too, the combination of <a href="https://twitter.com/hashtag/PDL1?src=hash&ref_src=twsrc%5Etfw">#PDL1</a> and <a href="https://twitter.com/hashtag/CD80?src=hash&ref_src=twsrc%5Etfw">#CD80</a> molecules that cannot interact with each other allowed more vigorous <a href="https://twitter.com/hashtag/inhibition?src=hash&ref_src=twsrc%5Etfw">#inhibition</a> of IL-2 production by T cells. <a href="https://twitter.com/hashtag/Mechanistically?src=hash&ref_src=twsrc%5Etfw">#Mechanistically</a>, it showed that 'liberated' PDL1 on DCs cross-interacts with PD1 on T cell and <a href="https://twitter.com/hashtag/inhibits?src=hash&ref_src=twsrc%5Etfw">#inhibits</a> it. <a href="https://t.co/YxM6oskg3q">pic.twitter.com/YxM6oskg3q</a></div>
— David Usharauli (@3DiMMUNE) <a href="https://twitter.com/3DiMMUNE/status/1120839326059978757?ref_src=twsrc%5Etfw">April 23, 2019</a></blockquote>
<script async="" charset="utf-8" src="https://platform.twitter.com/widgets.js"></script>
<br />
<blockquote class="twitter-tweet tw-align-center" data-lang="en">
<div dir="ltr" lang="en">
7. Similarly, mice expressing mutant PDL1 or CD80 molecules showed reduced inflammation in the brain [in <a href="https://twitter.com/hashtag/EAE?src=hash&ref_src=twsrc%5Etfw">#EAE</a> <a href="https://twitter.com/hashtag/model?src=hash&ref_src=twsrc%5Etfw">#model</a>] after priming with brain-specific antigens though the effect seems to be minimal. <a href="https://t.co/P2fyIusL1M">pic.twitter.com/P2fyIusL1M</a></div>
— David Usharauli (@3DiMMUNE) <a href="https://twitter.com/3DiMMUNE/status/1120839329667014662?ref_src=twsrc%5Etfw">April 23, 2019</a></blockquote>
<script async="" charset="utf-8" src="https://platform.twitter.com/widgets.js"></script>
<br />
<blockquote class="twitter-tweet tw-align-center" data-lang="en">
<div dir="ltr" lang="en">
It indicates PDL1 <a href="https://twitter.com/hashtag/sequestration?src=hash&ref_src=twsrc%5Etfw">#sequestration</a> by CD80 on DCs is not a major path that controls immunity in <a href="https://twitter.com/hashtag/physiological?src=hash&ref_src=twsrc%5Etfw">#physiological</a> condition. The authors did not show if it undermines protection against <a href="https://twitter.com/hashtag/pathogens?src=hash&ref_src=twsrc%5Etfw">#pathogens</a> or <a href="https://twitter.com/hashtag/tolerance?src=hash&ref_src=twsrc%5Etfw">#tolerance</a> to gut <a href="https://twitter.com/hashtag/commensals?src=hash&ref_src=twsrc%5Etfw">#commensals</a>.</div>
— David Usharauli (@3DiMMUNE) <a href="https://twitter.com/3DiMMUNE/status/1120839331894239232?ref_src=twsrc%5Etfw">April 23, 2019</a></blockquote>
<script async="" charset="utf-8" src="https://platform.twitter.com/widgets.js"></script>
David Usharaulihttp://www.blogger.com/profile/02668672470276307921noreply@blogger.com0tag:blogger.com,1999:blog-6821948329541212415.post-27998511869233962342019-04-20T18:32:00.000-04:002019-05-07T16:49:31.459-04:00Crohn's disease-like phenotype could be initiated by one gut microbe in genetically susceptible mice<blockquote class="twitter-tweet tw-align-center" data-lang="en">
<div dir="ltr" lang="en">
1. The authors used doubly deficient Nod2−/−Cybb−/− [NADPH oxidase] (DKO) mice (genes thought to be altered in <a href="https://twitter.com/hashtag/Crohns?src=hash&ref_src=twsrc%5Etfw">#Crohns</a>). When fostered with Taconic dams, but not Jax dams, these DKO pups get spontaneous gut <a href="https://twitter.com/hashtag/inflammation?src=hash&ref_src=twsrc%5Etfw">#inflammation</a> after weaning (3 weeks post birth). <a href="https://t.co/LdoBA8Dfao">pic.twitter.com/LdoBA8Dfao</a></div>
— David Usharauli (@3DiMMUNE) <a href="https://twitter.com/3DiMMUNE/status/1119727063911550977?ref_src=twsrc%5Etfw">April 20, 2019</a></blockquote>
<script async="" charset="utf-8" src="https://platform.twitter.com/widgets.js"></script>
<br />
<blockquote class="twitter-tweet tw-align-center" data-lang="en">
<div dir="ltr" lang="en">
3. using the <a href="https://twitter.com/hashtag/microbiota?src=hash&ref_src=twsrc%5Etfw">#microbiota</a> analysis tool (linear discriminant analysis<br />(LDA) effect size (<a href="https://twitter.com/hashtag/LEfSe?src=hash&ref_src=twsrc%5Etfw">#LEfSe</a>) methodology) the author found that one particular microbiota species, M. schaedleri, showed 1349-fold enrichment in DKO mice but not in single KOs. <a href="https://t.co/BzMUB63cGf">pic.twitter.com/BzMUB63cGf</a></div>
— David Usharauli (@3DiMMUNE) <a href="https://twitter.com/3DiMMUNE/status/1119727066864345089?ref_src=twsrc%5Etfw">April 20, 2019</a></blockquote>
<script async="" charset="utf-8" src="https://platform.twitter.com/widgets.js"></script>
<br />
<blockquote class="twitter-tweet tw-align-center" data-lang="en">
<div dir="ltr" lang="en">
5. Time analysis showed that DKO pups fostered with Tac dams harbor M. schaedleri-specific IgA and IgG but only before weaning. These <a href="https://twitter.com/hashtag/antibody?src=hash&ref_src=twsrc%5Etfw">#antibody</a> titers quickly decline post weaning that correlated with the onset of <a href="https://twitter.com/hashtag/CrohnsDisease?src=hash&ref_src=twsrc%5Etfw">#CrohnsDisease</a>-like phenotype. <a href="https://t.co/elMRXdMdv3">pic.twitter.com/elMRXdMdv3</a></div>
— David Usharauli (@3DiMMUNE) <a href="https://twitter.com/3DiMMUNE/status/1119727070307917827?ref_src=twsrc%5Etfw">April 20, 2019</a></blockquote>
<script async="" charset="utf-8" src="https://platform.twitter.com/widgets.js"></script>
<br />
<blockquote class="twitter-tweet tw-align-center" data-lang="en">
<div dir="ltr" lang="en">
In summary, this study showed that <a href="https://twitter.com/hashtag/spontaneous?src=hash&ref_src=twsrc%5Etfw">#spontaneous</a> gut <a href="https://twitter.com/hashtag/inflammation?src=hash&ref_src=twsrc%5Etfw">#inflammation</a> could be recapitulated in mice doubly deficient for two specific genes, <a href="https://twitter.com/hashtag/NOD2?src=hash&ref_src=twsrc%5Etfw">#NOD2</a> and <a href="https://twitter.com/hashtag/NADPH?src=hash&ref_src=twsrc%5Etfw">#NADPH</a> oxidase and exposed to specific gut <a href="https://twitter.com/hashtag/microbiota?src=hash&ref_src=twsrc%5Etfw">#microbiota</a>, Mucispirillum schaedleri.</div>
— David Usharauli (@3DiMMUNE) <a href="https://twitter.com/3DiMMUNE/status/1119727073646477317?ref_src=twsrc%5Etfw">April 20, 2019</a></blockquote>
<script async="" charset="utf-8" src="https://platform.twitter.com/widgets.js"></script>
<br />
<blockquote class="twitter-tweet tw-align-center" data-lang="en">
<div dir="ltr" lang="en">
So, here we have a complete model of spontaneous gut inflammation initiated by a particular gut microbe in a genetically susceptible host. Is it how <a href="https://twitter.com/hashtag/CrohnsDisease?src=hash&ref_src=twsrc%5Etfw">#CrohnsDisease</a> develops too in humans?</div>
— David Usharauli (@3DiMMUNE) <a href="https://twitter.com/3DiMMUNE/status/1119727075185823746?ref_src=twsrc%5Etfw">April 20, 2019</a></blockquote>
<script async="" charset="utf-8" src="https://platform.twitter.com/widgets.js"></script>
David Usharaulihttp://www.blogger.com/profile/02668672470276307921noreply@blogger.com0tag:blogger.com,1999:blog-6821948329541212415.post-37560937631013596752019-04-03T19:48:00.001-04:002019-05-07T16:49:48.166-04:00Innate help to Tregs in the gut<blockquote class="twitter-tweet tw-align-center" data-lang="en">
<div dir="ltr" lang="en">
New study in <a href="https://twitter.com/nature?ref_src=twsrc%5Etfw">@Nature</a> indicates gut <a href="https://twitter.com/hashtag/ILC3?src=hash&ref_src=twsrc%5Etfw">#ILC3</a> (type 3 innate lymphoid cells) produce IL-2 for <a href="https://twitter.com/hashtag/FOXP3?src=hash&ref_src=twsrc%5Etfw">#FOXP3</a>+ Tregs. Is it relevant? lets discuss it. <a href="https://twitter.com/hashtag/Immunology?src=hash&ref_src=twsrc%5Etfw">#Immunology</a> <a href="https://twitter.com/hashtag/tolerance?src=hash&ref_src=twsrc%5Etfw">#tolerance</a> <a href="https://twitter.com/hashtag/microbiota?src=hash&ref_src=twsrc%5Etfw">#microbiota</a> <a href="https://t.co/iziPJb09Zy">https://t.co/iziPJb09Zy</a></div>
— David Usharauli (@3DiMMUNE) <a href="https://twitter.com/3DiMMUNE/status/1113573023913840642?ref_src=twsrc%5Etfw">April 3, 2019</a></blockquote>
<script async="" charset="utf-8" src="https://platform.twitter.com/widgets.js"></script>
<br />
<blockquote class="twitter-tweet tw-align-center" data-lang="en">
<div dir="ltr" lang="en">
2. Interestingly, the <a href="https://twitter.com/hashtag/frequency?src=hash&ref_src=twsrc%5Etfw">#frequency</a> of IL-2-producing ILC3s was depended on the presence of <a href="https://twitter.com/hashtag/microbiota?src=hash&ref_src=twsrc%5Etfw">#microbiota</a>. Specifically, the authors showed that <a href="https://twitter.com/hashtag/cytokine?src=hash&ref_src=twsrc%5Etfw">#cytokine</a> IL-1 produced by <a href="https://twitter.com/hashtag/macrophages?src=hash&ref_src=twsrc%5Etfw">#macrophages</a> signaled ILC3 to produce IL-2. <a href="https://twitter.com/hashtag/MyD88?src=hash&ref_src=twsrc%5Etfw">#MyD88</a> was involved (it is needed to produce IL-1 anyway). <a href="https://t.co/dGb66Pqnwt">pic.twitter.com/dGb66Pqnwt</a></div>
— David Usharauli (@3DiMMUNE) <a href="https://twitter.com/3DiMMUNE/status/1113573025901891591?ref_src=twsrc%5Etfw">April 3, 2019</a></blockquote>
<script async="" charset="utf-8" src="https://platform.twitter.com/widgets.js"></script>
<br />
<blockquote class="twitter-tweet tw-align-center" data-lang="en">
<div dir="ltr" lang="en">
4. However, it is clear that IL-2 inactivation in NCR1-cre mouse is not clean and some ILC3 retain a capacity to secrete IL-2 (otherwise there should not be any IL-2+ ILC3 in this graph). <a href="https://t.co/Zwbz2dDP3n">pic.twitter.com/Zwbz2dDP3n</a></div>
— David Usharauli (@3DiMMUNE) <a href="https://twitter.com/3DiMMUNE/status/1113573028963803136?ref_src=twsrc%5Etfw">April 3, 2019</a></blockquote>
<script async="" charset="utf-8" src="https://platform.twitter.com/widgets.js"></script>
<br />
<blockquote class="twitter-tweet tw-align-center" data-lang="en">
<div dir="ltr" lang="en">
6. To complete the story the authors showed that individuals with <a href="https://twitter.com/hashtag/Crohn?src=hash&ref_src=twsrc%5Etfw">#Crohn</a>'s disease harbor fewer ILC3 that produce IL-2 to feed Tregs in the small intestine suggesting that one reason why CDs could generate <a href="https://twitter.com/hashtag/inflammatory?src=hash&ref_src=twsrc%5Etfw">#inflammatory</a> condition. <a href="https://t.co/k2LN2LeMFe">pic.twitter.com/k2LN2LeMFe</a></div>
— David Usharauli (@3DiMMUNE) <a href="https://twitter.com/3DiMMUNE/status/1113573031639699457?ref_src=twsrc%5Etfw">April 3, 2019</a></blockquote>
<script async="" charset="utf-8" src="https://platform.twitter.com/widgets.js"></script>
<br />
<blockquote class="twitter-tweet tw-align-center" data-lang="en">
<div dir="ltr" lang="en">
in summary, this study showed that ILC3-produced IL-2 could support Treg functionality in the small intestine. This cooperation between ILC3 and Tregs appears to be antigen-nonspecific as mice with ILC3 deficient for MHCII does not show changes in Tregs. 1/3</div>
— David Usharauli (@3DiMMUNE) <a href="https://twitter.com/3DiMMUNE/status/1113573034625990656?ref_src=twsrc%5Etfw">April 3, 2019</a></blockquote>
<script async="" charset="utf-8" src="https://platform.twitter.com/widgets.js"></script>
<br />
<blockquote class="twitter-tweet tw-align-center" data-lang="en">
<div dir="ltr" lang="en">
I like to point out that out of so many figures only 1 figure shows a reduction of Treg numbers in the small intestine that supports the authors' claims of the role of ILC3-derived IL-2 in Treg homeostasis, the rest are shown as % (not optimal) or does not support claims. 3/3</div>
— David Usharauli (@3DiMMUNE) <a href="https://twitter.com/3DiMMUNE/status/1113573035787866112?ref_src=twsrc%5Etfw">April 3, 2019</a></blockquote>
<script async="" charset="utf-8" src="https://platform.twitter.com/widgets.js"></script>
David Usharaulihttp://www.blogger.com/profile/02668672470276307921noreply@blogger.com0tag:blogger.com,1999:blog-6821948329541212415.post-84919501536617638032019-03-21T19:18:00.001-04:002019-03-21T19:18:08.945-04:00A physiological T cells' "weaning reaction" to microbiota and solid foods in newborn pups requires FOXP3+ Tregs <blockquote class="twitter-tweet tw-align-center" data-lang="en">
<div dir="ltr" lang="en">
1. "weaning reaction" is described as a <a href="https://twitter.com/hashtag/physiological?src=hash&ref_src=twsrc%5Etfw">#physiological</a> CD4+ T cell response to to <a href="https://twitter.com/hashtag/microbiota?src=hash&ref_src=twsrc%5Etfw">#microbiota</a>+solid <a href="https://twitter.com/hashtag/foods?src=hash&ref_src=twsrc%5Etfw">#foods</a> in mouse pups that occurs between 2-4 weeks after birth measured by analysis of <a href="https://twitter.com/hashtag/TNF?src=hash&ref_src=twsrc%5Etfw">#TNF</a>-alpha and <a href="https://twitter.com/hashtag/IFN?src=hash&ref_src=twsrc%5Etfw">#IFN</a>-gamma levels. It does not occur in <a href="https://twitter.com/hashtag/germfree?src=hash&ref_src=twsrc%5Etfw">#germfree</a> pups devoid of microbiota. <a href="https://t.co/pSGWXOUBoC">pic.twitter.com/pSGWXOUBoC</a></div>
— David Usharauli (@3DiMMUNE) <a href="https://twitter.com/3DiMMUNE/status/1108863049920901123?ref_src=twsrc%5Etfw">March 21, 2019</a></blockquote>
<script async="" charset="utf-8" src="https://platform.twitter.com/widgets.js"></script>
<br />
<blockquote class="twitter-tweet tw-align-center" data-lang="en">
<div dir="ltr" lang="en">
3. More importantly, however, <a href="https://twitter.com/hashtag/microbiota?src=hash&ref_src=twsrc%5Etfw">#microbiota</a> exposure between 2-4 weeks after birth but not later could restore <a href="https://twitter.com/hashtag/physiological?src=hash&ref_src=twsrc%5Etfw">#physiological</a> "<a href="https://twitter.com/hashtag/weaning?src=hash&ref_src=twsrc%5Etfw">#weaning</a> reaction" in T cells in <a href="https://twitter.com/hashtag/germfree?src=hash&ref_src=twsrc%5Etfw">#germfree</a> pups. <a href="https://twitter.com/hashtag/tolerance?src=hash&ref_src=twsrc%5Etfw">#tolerance</a> <a href="https://twitter.com/hashtag/immunology?src=hash&ref_src=twsrc%5Etfw">#immunology</a> <a href="https://t.co/9KUtk3MT7R">pic.twitter.com/9KUtk3MT7R</a></div>
— David Usharauli (@3DiMMUNE) <a href="https://twitter.com/3DiMMUNE/status/1108863053028868097?ref_src=twsrc%5Etfw">March 21, 2019</a></blockquote>
<script async="" charset="utf-8" src="https://platform.twitter.com/widgets.js"></script>
<br />
<blockquote class="twitter-tweet tw-align-center" data-lang="en">
<div dir="ltr" lang="en">
5. Interestingly, "weaning reaction" in <a href="https://twitter.com/hashtag/newborn?src=hash&ref_src=twsrc%5Etfw">#newborn</a> pups were dependent on presence of gut residing RORgt+ FOXP3+ T regulatory cells (Tregs). <a href="https://twitter.com/hashtag/tolerance?src=hash&ref_src=twsrc%5Etfw">#tolerance</a> <a href="https://t.co/s1nq2HPShK">pic.twitter.com/s1nq2HPShK</a></div>
— David Usharauli (@3DiMMUNE) <a href="https://twitter.com/3DiMMUNE/status/1108863056031961089?ref_src=twsrc%5Etfw">March 21, 2019</a></blockquote>
<script async="" charset="utf-8" src="https://platform.twitter.com/widgets.js"></script>
<br />
<blockquote class="twitter-tweet tw-align-center" data-lang="en">
<div dir="ltr" lang="en">
2nd Correction (#6): giving <a href="https://twitter.com/hashtag/SCFAs?src=hash&ref_src=twsrc%5Etfw">#SCFAs</a> to <a href="https://twitter.com/hashtag/antibiotic?src=hash&ref_src=twsrc%5Etfw">#antibiotic</a>-treated newborn pups could prevent <a href="https://twitter.com/hashtag/inflammation?src=hash&ref_src=twsrc%5Etfw">#inflammation</a> later. It appears this effect of SCFAs requires <a href="https://twitter.com/hashtag/Tregs?src=hash&ref_src=twsrc%5Etfw">#Tregs</a> and <a href="https://twitter.com/hashtag/microbiota?src=hash&ref_src=twsrc%5Etfw">#microbiota</a> (it does not work in GF pups) that provides <a href="https://twitter.com/hashtag/antigens?src=hash&ref_src=twsrc%5Etfw">#antigens</a> to Tregs to keeps them in <a href="https://twitter.com/hashtag/functioning?src=hash&ref_src=twsrc%5Etfw">#functioning</a> state. <a href="https://t.co/2ewMoDRobh">pic.twitter.com/2ewMoDRobh</a></div>
— David Usharauli (@3DiMMUNE) <a href="https://twitter.com/3DiMMUNE/status/1108867918832590848?ref_src=twsrc%5Etfw">March 21, 2019</a></blockquote>
<script async="" charset="utf-8" src="https://platform.twitter.com/widgets.js"></script>
<br />
<blockquote class="twitter-tweet tw-align-center" data-lang="en">
<div dir="ltr" lang="en">
This suggests that the effect of SCFAs is mediated via Tregs and that artifically generated "weaning reaction" with SCFAs without proper Treg contribution (driven by microbiota and their antigens) is not optimal.</div>
— David Usharauli (@3DiMMUNE) <a href="https://twitter.com/3DiMMUNE/status/1108863059941052420?ref_src=twsrc%5Etfw">March 21, 2019</a></blockquote>
<script async="" charset="utf-8" src="https://platform.twitter.com/widgets.js"></script>
David Usharaulihttp://www.blogger.com/profile/02668672470276307921noreply@blogger.com0tag:blogger.com,1999:blog-6821948329541212415.post-13440828238420458452019-03-05T16:29:00.001-05:002019-03-05T16:29:16.589-05:00β-synuclein specific CD4+ T cells invade brain grey matter to cause array of MS-like symptoms<blockquote class="twitter-tweet tw-align-center" data-lang="en">
<div dir="ltr" lang="en">
β-synuclein specific CD4+ T cells invade <a href="https://twitter.com/hashtag/brain?src=hash&ref_src=twsrc%5Etfw">#brain</a> grey matter and cause array of MS-like <a href="https://twitter.com/hashtag/symptoms?src=hash&ref_src=twsrc%5Etfw">#symptoms</a> in a rat model of human <a href="https://twitter.com/hashtag/MultipleSclerosis?src=hash&ref_src=twsrc%5Etfw">#MultipleSclerosis</a>. Interestingly, the most useful distilled data points were in suppl materials. <a href="https://twitter.com/hashtag/immunology?src=hash&ref_src=twsrc%5Etfw">#immunology</a> <a href="https://twitter.com/hashtag/autoimmunedisease?src=hash&ref_src=twsrc%5Etfw">#autoimmunedisease</a> <a href="https://t.co/NbIt5ijxuR">https://t.co/NbIt5ijxuR</a></div>
— David Usharauli (@3DiMMUNE) <a href="https://twitter.com/3DiMMUNE/status/1103041419596521476?ref_src=twsrc%5Etfw">March 5, 2019</a></blockquote>
<script async="" charset="utf-8" src="https://platform.twitter.com/widgets.js"></script>
<br />
<blockquote class="twitter-tweet tw-align-center" data-lang="en">
<div dir="ltr" lang="en">
highlights from paper<br />2. Such exclusive invasion of brain grey matter were primarily correlated by pattern of <a href="https://twitter.com/hashtag/antigen?src=hash&ref_src=twsrc%5Etfw">#antigen</a> (β-synuclein) expression. <a href="https://twitter.com/hashtag/autoimmunedisease?src=hash&ref_src=twsrc%5Etfw">#autoimmunedisease</a> <a href="https://twitter.com/hashtag/immunology?src=hash&ref_src=twsrc%5Etfw">#immunology</a> <a href="https://t.co/1r9ROgtTDV">pic.twitter.com/1r9ROgtTDV</a></div>
— David Usharauli (@3DiMMUNE) <a href="https://twitter.com/3DiMMUNE/status/1103041421664272384?ref_src=twsrc%5Etfw">March 5, 2019</a></blockquote>
<script async="" charset="utf-8" src="https://platform.twitter.com/widgets.js"></script>
<br />
<blockquote class="twitter-tweet tw-align-center" data-lang="en">
<div dir="ltr" lang="en">
Some thoughts: here the authors have used either WT or transgenic rat expressing β-synuclein-specific T cells. Diseases were induced either following direct immunization of transgenic rats or adoptive transfer of activated β-<a href="https://twitter.com/hashtag/synuclein?src=hash&ref_src=twsrc%5Etfw">#synuclein</a>-specific T cell blasts. <a href="https://twitter.com/hashtag/immunology?src=hash&ref_src=twsrc%5Etfw">#immunology</a></div>
— David Usharauli (@3DiMMUNE) <a href="https://twitter.com/3DiMMUNE/status/1103041425615278080?ref_src=twsrc%5Etfw">March 5, 2019</a></blockquote>
<script async="" charset="utf-8" src="https://platform.twitter.com/widgets.js"></script>
<br />
<blockquote class="twitter-tweet tw-align-center" data-lang="en">
<div dir="ltr" lang="en">
Con't: immunologists have fairly good idea about processes that represent immune response but at presently it is still unknown how immune response is <a href="https://twitter.com/hashtag/initiated?src=hash&ref_src=twsrc%5Etfw">#initiated</a> naturally or how it is <a href="https://twitter.com/hashtag/stopped?src=hash&ref_src=twsrc%5Etfw">#stopped</a>. This is Achilles heels of current experimental models in <a href="https://twitter.com/hashtag/immunology?src=hash&ref_src=twsrc%5Etfw">#immunology</a>.</div>
— David Usharauli (@3DiMMUNE) <a href="https://twitter.com/3DiMMUNE/status/1103041427100045312?ref_src=twsrc%5Etfw">March 5, 2019</a></blockquote>
<script async="" charset="utf-8" src="https://platform.twitter.com/widgets.js"></script>
David Usharaulihttp://www.blogger.com/profile/02668672470276307921noreply@blogger.com0tag:blogger.com,1999:blog-6821948329541212415.post-91909480737151801572019-02-23T19:18:00.000-05:002019-02-23T19:18:02.236-05:00IL-17 response to airborne fungi are driven by gut commensal pathobiont C. albicans <blockquote class="twitter-tweet tw-align-center" data-lang="en">
<div dir="ltr" lang="en">
A new paper in <a href="https://twitter.com/CellCellPress?ref_src=twsrc%5Etfw">@CellCellPress</a> from Bacher/Scheffold lab showed that IL-17+ T cell response to airborne <a href="https://twitter.com/hashtag/fungus?src=hash&ref_src=twsrc%5Etfw">#fungus</a> such as <a href="https://twitter.com/hashtag/Aspergillus?src=hash&ref_src=twsrc%5Etfw">#Aspergillus</a> fumigatus found in individuals with <a href="https://twitter.com/hashtag/asthma?src=hash&ref_src=twsrc%5Etfw">#asthma</a>,<a href="https://twitter.com/hashtag/COPD?src=hash&ref_src=twsrc%5Etfw">#COPD</a>, and CF,are in fact expanded by gut commensal pathobiont <a href="https://twitter.com/hashtag/Candida?src=hash&ref_src=twsrc%5Etfw">#Candida</a> <a href="https://twitter.com/hashtag/albicans?src=hash&ref_src=twsrc%5Etfw">#albicans</a> via <a href="https://twitter.com/hashtag/crossreactivity?src=hash&ref_src=twsrc%5Etfw">#crossreactivity</a>.</div>
— David Usharauli (@3DiMMUNE) <a href="https://twitter.com/3DiMMUNE/status/1099454679757582336?ref_src=twsrc%5Etfw">February 23, 2019</a></blockquote>
<script async="" charset="utf-8" src="https://platform.twitter.com/widgets.js"></script>
<br />
<blockquote class="twitter-tweet tw-align-center" data-lang="en">
<div dir="ltr" lang="en">
1. majority of IL-17+ <a href="https://twitter.com/hashtag/Tcells?src=hash&ref_src=twsrc%5Etfw">#Tcells</a> found in healthy donors are specific C. albicans. <a href="https://twitter.com/hashtag/Immunology?src=hash&ref_src=twsrc%5Etfw">#Immunology</a> <a href="https://twitter.com/hashtag/TH17?src=hash&ref_src=twsrc%5Etfw">#TH17</a> <a href="https://twitter.com/hashtag/fungi?src=hash&ref_src=twsrc%5Etfw">#fungi</a> <a href="https://t.co/3WITidrcCn">pic.twitter.com/3WITidrcCn</a></div>
— David Usharauli (@3DiMMUNE) <a href="https://twitter.com/3DiMMUNE/status/1099454681024286727?ref_src=twsrc%5Etfw">February 23, 2019</a></blockquote>
<script async="" charset="utf-8" src="https://platform.twitter.com/widgets.js"></script>
<br />
<blockquote class="twitter-tweet tw-align-center" data-lang="en">
<div dir="ltr" lang="en">
3. In fact, when C. albicans-specific T cells were depleted from <a href="https://twitter.com/hashtag/Aspergillus?src=hash&ref_src=twsrc%5Etfw">#Aspergillus</a> fumigatus-specific T cell pool IL-17 response was gone too suggesting that most if not all of IL-17+ T cells specific for A. fumigatus were indeed <a href="https://twitter.com/hashtag/crossreactive?src=hash&ref_src=twsrc%5Etfw">#crossreactive</a> to C. albicans. <a href="https://t.co/cZEu50Uwep">pic.twitter.com/cZEu50Uwep</a></div>
— David Usharauli (@3DiMMUNE) <a href="https://twitter.com/3DiMMUNE/status/1099454684602028033?ref_src=twsrc%5Etfw">February 23, 2019</a></blockquote>
<script async="" charset="utf-8" src="https://platform.twitter.com/widgets.js"></script>
<br />
<blockquote class="twitter-tweet tw-align-center" data-lang="en">
<div dir="ltr" lang="en">
5. similar expansion of Aspergillus fumigatus-specific T cells producing IL-17 were observed in individuals with <a href="https://twitter.com/hashtag/crohnsdisease?src=hash&ref_src=twsrc%5Etfw">#crohnsdisease</a> too. <a href="https://t.co/L0VbmCcFj5">pic.twitter.com/L0VbmCcFj5</a></div>
— David Usharauli (@3DiMMUNE) <a href="https://twitter.com/3DiMMUNE/status/1099454688628490240?ref_src=twsrc%5Etfw">February 23, 2019</a></blockquote>
<script async="" charset="utf-8" src="https://platform.twitter.com/widgets.js"></script>
<br />
<blockquote class="twitter-tweet tw-align-center" data-lang="en">
<div dir="ltr" lang="en">
As both <a href="https://twitter.com/hashtag/fungi?src=hash&ref_src=twsrc%5Etfw">#fungi</a> are naturally available in the environment any <a href="https://twitter.com/hashtag/immunopathology?src=hash&ref_src=twsrc%5Etfw">#immunopathology</a> driven by excess of IL-17 response must be the result of some other changes in the host that makes it susceptible to pathology. what???</div>
— David Usharauli (@3DiMMUNE) <a href="https://twitter.com/3DiMMUNE/status/1099454690742493184?ref_src=twsrc%5Etfw">February 23, 2019</a></blockquote>
<script async="" charset="utf-8" src="https://platform.twitter.com/widgets.js"></script>
David Usharaulihttp://www.blogger.com/profile/02668672470276307921noreply@blogger.com0tag:blogger.com,1999:blog-6821948329541212415.post-46137965913081853462019-02-16T17:56:00.000-05:002019-02-16T17:56:11.828-05:00No going back: conventional B cells (B2) could trans-differentiate into innate-like B cells (B1) but not vice versa<blockquote class="twitter-tweet tw-align-center" data-lang="en">
<div dir="ltr" lang="en">
The study is about origin of B1vs.B2 cells. B1 cells are innate-like B cell lineage that reside in peritoneal & pleural cavities and express restricted BCRs specific for conserved molecules such as phosphatidylcholine. B2 cells are conventional B cells expressing diverse of BCR.</div>
— David Usharauli (@3DiMMUNE) <a href="https://twitter.com/3DiMMUNE/status/1096900660400979968?ref_src=twsrc%5Etfw">February 16, 2019</a></blockquote>
<script async="" charset="utf-8" src="https://platform.twitter.com/widgets.js"></script>
<br />
<blockquote class="twitter-tweet tw-align-center" data-lang="en">
<div dir="ltr" lang="en">
1. This is a model system the authors set up to do it. Normally, <a href="https://twitter.com/hashtag/transgenic?src=hash&ref_src=twsrc%5Etfw">#transgenic</a> B cells express either VH12 (B1) or B1-8 (B2) only. However, after cre <a href="https://twitter.com/hashtag/recombination?src=hash&ref_src=twsrc%5Etfw">#recombination</a>, VH12 is <a href="https://twitter.com/hashtag/replaced?src=hash&ref_src=twsrc%5Etfw">#replaced</a> with B1-8 and vice versa. So, B1 should start expressing B2 receptor and B2 --> B1 receptor. <a href="https://t.co/L4J1nBJENh">pic.twitter.com/L4J1nBJENh</a></div>
— David Usharauli (@3DiMMUNE) <a href="https://twitter.com/3DiMMUNE/status/1096900661671804928?ref_src=twsrc%5Etfw">February 16, 2019</a></blockquote>
<script async="" charset="utf-8" src="https://platform.twitter.com/widgets.js"></script>
<br />
<blockquote class="twitter-tweet tw-align-center" data-lang="en">
<div dir="ltr" lang="en">
3. The same outcome was observed in an in <a href="https://twitter.com/hashtag/vivo?src=hash&ref_src=twsrc%5Etfw">#vivo</a> setting too. Conventional B2 cells could produce <a href="https://twitter.com/hashtag/functioning?src=hash&ref_src=twsrc%5Etfw">#functioning</a> B1 cells after <a href="https://twitter.com/hashtag/BCR?src=hash&ref_src=twsrc%5Etfw">#BCR</a> swap but not vice versa. <a href="https://t.co/cXHJLWaHsv">pic.twitter.com/cXHJLWaHsv</a></div>
— David Usharauli (@3DiMMUNE) <a href="https://twitter.com/3DiMMUNE/status/1096900664926580741?ref_src=twsrc%5Etfw">February 16, 2019</a></blockquote>
<script async="" charset="utf-8" src="https://platform.twitter.com/widgets.js"></script>
<br />
<blockquote class="twitter-tweet tw-align-center" data-lang="en">
<div dir="ltr" lang="en">
<a href="https://twitter.com/hashtag/Summary?src=hash&ref_src=twsrc%5Etfw">#Summary</a>: conventional B cells (a.k.a B2 cells) still harbor <a href="https://twitter.com/hashtag/potential?src=hash&ref_src=twsrc%5Etfw">#potential</a> for trans-differentiate into B1 cells while B1 cells lack such quality. <br /><br />Why is that? B1 produce so called natural "housekeeping" antibodies specific for some self antigens exposed during cell <a href="https://twitter.com/hashtag/senescence?src=hash&ref_src=twsrc%5Etfw">#senescence</a>.</div>
— David Usharauli (@3DiMMUNE) <a href="https://twitter.com/3DiMMUNE/status/1096900669540352001?ref_src=twsrc%5Etfw">February 16, 2019</a></blockquote>
<script async="" charset="utf-8" src="https://platform.twitter.com/widgets.js"></script>
<br />
<blockquote class="twitter-tweet tw-align-center" data-lang="en">
<div dir="ltr" lang="en">
B2 cells, on the other hand, if happened to express B1-like receptor it could end up in B1 pool. Then it would acquire B1 functioning and develop into regulatory B cell category joining other B1 cells. In other word, To be a B1 cells is to be a good B cells by definition 😎</div>
— David Usharauli (@3DiMMUNE) <a href="https://twitter.com/3DiMMUNE/status/1096900671213895680?ref_src=twsrc%5Etfw">February 16, 2019</a></blockquote>
<script async="" charset="utf-8" src="https://platform.twitter.com/widgets.js"></script>
David Usharaulihttp://www.blogger.com/profile/02668672470276307921noreply@blogger.com0tag:blogger.com,1999:blog-6821948329541212415.post-5054311281434739462019-02-09T17:29:00.001-05:002019-02-09T17:29:05.100-05:00An antigen from gut commensal Bacteroides thetaiotaomicron (B. theta) is recognized by Foxp3+ Tregs<blockquote class="twitter-tweet tw-align-center" data-lang="en">
<div dir="ltr" lang="en">
1. B.theta-specific T cells when transferred into <a href="https://twitter.com/hashtag/antibiotic?src=hash&ref_src=twsrc%5Etfw">#antibiotic</a>-treated and B.theta <a href="https://twitter.com/hashtag/colonized?src=hash&ref_src=twsrc%5Etfw">#colonized</a> T cell-deficient mice (<a href="https://twitter.com/hashtag/RAG1?src=hash&ref_src=twsrc%5Etfw">#RAG1</a>-KO) develop into <a href="https://twitter.com/hashtag/Foxp3?src=hash&ref_src=twsrc%5Etfw">#Foxp3</a>+ <a href="https://twitter.com/hashtag/Tregs?src=hash&ref_src=twsrc%5Etfw">#Tregs</a> as well as effector T cells. It is not clear if donor tg T cells were on RAG1-KO background as well. Host mice stay healthy. <a href="https://t.co/TD0pnnxgAR">pic.twitter.com/TD0pnnxgAR</a></div>
— David Usharauli (@3DiMMUNE) <a href="https://twitter.com/3DiMMUNE/status/1094360313011556354?ref_src=twsrc%5Etfw">February 9, 2019</a></blockquote>
<script async="" charset="utf-8" src="https://platform.twitter.com/widgets.js"></script>
<br />
<blockquote class="twitter-tweet tw-align-center" data-lang="en">
<div dir="ltr" lang="en">
3. The authors were able to identify a <a href="https://twitter.com/hashtag/specific?src=hash&ref_src=twsrc%5Etfw">#specific</a> <a href="https://twitter.com/hashtag/epitope?src=hash&ref_src=twsrc%5Etfw">#epitope</a> in B.theta recognized by B.theta-specific T cells. The <a href="https://twitter.com/hashtag/sequence?src=hash&ref_src=twsrc%5Etfw">#sequence</a>, EEFNLPTTNGGHAT, were mapped in BT4295 predicted to be a SusE/SusF <a href="https://twitter.com/hashtag/lipoprotein?src=hash&ref_src=twsrc%5Etfw">#lipoprotein</a> in outer <a href="https://twitter.com/hashtag/membrane?src=hash&ref_src=twsrc%5Etfw">#membrane</a> (OM). <a href="https://t.co/rH5cQHQcVN">pic.twitter.com/rH5cQHQcVN</a></div>
— David Usharauli (@3DiMMUNE) <a href="https://twitter.com/3DiMMUNE/status/1094360317226815492?ref_src=twsrc%5Etfw">February 9, 2019</a></blockquote>
<script async="" charset="utf-8" src="https://platform.twitter.com/widgets.js"></script>
<br />
<blockquote class="twitter-tweet tw-align-center" data-lang="en">
<div dir="ltr" lang="en">
In <a href="https://twitter.com/hashtag/summary?src=hash&ref_src=twsrc%5Etfw">#summary</a>, this study showed that certain gut <a href="https://twitter.com/hashtag/commensal?src=hash&ref_src=twsrc%5Etfw">#commensal</a> <a href="https://twitter.com/hashtag/microbiota?src=hash&ref_src=twsrc%5Etfw">#microbiota</a> species, in this case, <a href="https://twitter.com/hashtag/Bacteroides?src=hash&ref_src=twsrc%5Etfw">#Bacteroides</a> thetaiotaomicron (B. theta) are recognized by <a href="https://twitter.com/hashtag/Tregs?src=hash&ref_src=twsrc%5Etfw">#Tregs</a> and even induce <a href="https://twitter.com/hashtag/effector?src=hash&ref_src=twsrc%5Etfw">#effector</a> T cell differentiation though the host stays healthy because Tregs regulate effector T cells.</div>
— David Usharauli (@3DiMMUNE) <a href="https://twitter.com/3DiMMUNE/status/1094360319697321984?ref_src=twsrc%5Etfw">February 9, 2019</a></blockquote>
<script async="" charset="utf-8" src="https://platform.twitter.com/widgets.js"></script>
<br />
<blockquote class="twitter-tweet tw-align-center" data-lang="en">
<div dir="ltr" lang="en">
Another point is whether <a href="https://twitter.com/hashtag/microbiota?src=hash&ref_src=twsrc%5Etfw">#microbiota</a>-specific Tregs are <a href="https://twitter.com/hashtag/denovo?src=hash&ref_src=twsrc%5Etfw">#denovo</a> induced or <a href="https://twitter.com/hashtag/amplified?src=hash&ref_src=twsrc%5Etfw">#amplified</a> from existing ones. I personally think it is a latter. Most <a href="https://twitter.com/hashtag/Tregs?src=hash&ref_src=twsrc%5Etfw">#Tregs</a> develop from <a href="https://twitter.com/hashtag/CD25?src=hash&ref_src=twsrc%5Etfw">#CD25</a>-negative <a href="https://twitter.com/hashtag/precursors?src=hash&ref_src=twsrc%5Etfw">#precursors</a> poised for Foxp3 expression & such precursors are all <a href="https://twitter.com/hashtag/thymus?src=hash&ref_src=twsrc%5Etfw">#thymus</a> derived, in my opinion.</div>
— David Usharauli (@3DiMMUNE) <a href="https://twitter.com/3DiMMUNE/status/1094360321068810240?ref_src=twsrc%5Etfw">February 9, 2019</a></blockquote>
<script async="" charset="utf-8" src="https://platform.twitter.com/widgets.js"></script>
David Usharaulihttp://www.blogger.com/profile/02668672470276307921noreply@blogger.com0tag:blogger.com,1999:blog-6821948329541212415.post-49810101479605110212019-01-24T17:40:00.000-05:002019-01-24T17:40:49.119-05:0011-strain consortium from human faecal microbiota drives IFN-gamma production in CD8 T cells<blockquote class="twitter-tweet tw-align-center" data-lang="en">
<div dir="ltr" lang="en">
New study <a href="https://twitter.com/nature?ref_src=twsrc%5Etfw">@nature</a> from Japanese scientists (Konda, Atarashi, & others) identified <a href="https://twitter.com/hashtag/consortium?src=hash&ref_src=twsrc%5Etfw">#consortium</a> (a nice clickbait for granting/funding agencies) of 11 microbial species from human faecal <a href="https://twitter.com/hashtag/microbiota?src=hash&ref_src=twsrc%5Etfw">#microbiota</a> that increase <a href="https://twitter.com/hashtag/IFN?src=hash&ref_src=twsrc%5Etfw">#IFN</a>-gamma+ <a href="https://twitter.com/hashtag/CD8?src=hash&ref_src=twsrc%5Etfw">#CD8</a> T cells protective against <a href="https://twitter.com/hashtag/infection?src=hash&ref_src=twsrc%5Etfw">#infection</a> and <a href="https://twitter.com/hashtag/tumors?src=hash&ref_src=twsrc%5Etfw">#tumors</a>.</div>
— David Usharauli (@3DiMMUNE) <a href="https://twitter.com/3DiMMUNE/status/1088559892326174725?ref_src=twsrc%5Etfw">January 24, 2019</a></blockquote>
<script async="" charset="utf-8" src="https://platform.twitter.com/widgets.js"></script>
<br />
<blockquote class="twitter-tweet tw-align-center" data-lang="en">
<div dir="ltr" lang="en">
2. Even these 11 strain <a href="https://twitter.com/hashtag/consortium?src=hash&ref_src=twsrc%5Etfw">#consortium</a> could be further narrowed down into two groups of 7 <a href="https://twitter.com/hashtag/Bacteroidales?src=hash&ref_src=twsrc%5Etfw">#Bacteroidales</a> and 4 non-Bacteroidales species. But effect on CD8 T cells was mostly lost when they were separated. <a href="https://t.co/UOzqWNFJQz">pic.twitter.com/UOzqWNFJQz</a></div>
— David Usharauli (@3DiMMUNE) <a href="https://twitter.com/3DiMMUNE/status/1088559895916564480?ref_src=twsrc%5Etfw">January 24, 2019</a></blockquote>
<script async="" charset="utf-8" src="https://platform.twitter.com/widgets.js"></script>
<br />
<blockquote class="twitter-tweet tw-align-center" data-lang="en">
<div dir="ltr" lang="en">
3. Significantly, effect of consortium on T cells were <a href="https://twitter.com/hashtag/biologically?src=hash&ref_src=twsrc%5Etfw">#biologically</a> relevant as it improved <a href="https://twitter.com/hashtag/protection?src=hash&ref_src=twsrc%5Etfw">#protection</a> against <a href="https://twitter.com/hashtag/pathogen?src=hash&ref_src=twsrc%5Etfw">#pathogen</a> challenge. <a href="https://t.co/Wotr8HJ4p5">pic.twitter.com/Wotr8HJ4p5</a></div>
— David Usharauli (@3DiMMUNE) <a href="https://twitter.com/3DiMMUNE/status/1088559900433805312?ref_src=twsrc%5Etfw">January 24, 2019</a></blockquote>
<script async="" charset="utf-8" src="https://platform.twitter.com/widgets.js"></script>
<br />
<blockquote class="twitter-tweet tw-align-center" data-lang="en">
<div dir="ltr" lang="en">
5. Though such <a href="https://twitter.com/hashtag/tumor?src=hash&ref_src=twsrc%5Etfw">#tumor</a> protective effect of this consortium alone was less obvious in SPF mice (regular lab mouse). But even in SPF mice combination of <a href="https://twitter.com/hashtag/consortium?src=hash&ref_src=twsrc%5Etfw">#consortium</a> + <a href="https://twitter.com/hashtag/checkpoint?src=hash&ref_src=twsrc%5Etfw">#checkpoint</a> inhibitors show a <a href="https://twitter.com/hashtag/synergy?src=hash&ref_src=twsrc%5Etfw">#synergy</a>. <a href="https://t.co/H9Iyv13E0o">pic.twitter.com/H9Iyv13E0o</a></div>
— David Usharauli (@3DiMMUNE) <a href="https://twitter.com/3DiMMUNE/status/1088559904682635266?ref_src=twsrc%5Etfw">January 24, 2019</a></blockquote>
<script async="" charset="utf-8" src="https://platform.twitter.com/widgets.js"></script>
<br />
<blockquote class="twitter-tweet tw-align-center" data-lang="en">
<div dir="ltr" lang="en">
scientifically speaking it is not very important paper. It lacks mechanisms & granularity typical for great papers.On the other hand,several authors including senior author are part of microbiota biotech company <a href="https://twitter.com/VedantaBio?ref_src=twsrc%5Etfw">@VedantaBio</a> and there these data might be sufficient for investment.</div>
— David Usharauli (@3DiMMUNE) <a href="https://twitter.com/3DiMMUNE/status/1088559907576692737?ref_src=twsrc%5Etfw">January 24, 2019</a></blockquote>
<script async="" charset="utf-8" src="https://platform.twitter.com/widgets.js"></script>
David Usharaulihttp://www.blogger.com/profile/02668672470276307921noreply@blogger.com0tag:blogger.com,1999:blog-6821948329541212415.post-58254390936421242272019-01-22T19:28:00.000-05:002019-01-22T19:28:42.761-05:00Two non-overlapping precursors generate Foxp3+ regulatory T cells in the thymus<blockquote class="twitter-tweet tw-align-center" data-cards="hidden" data-lang="en">
<div dir="ltr" lang="en">
New study in <a href="https://twitter.com/NatImmunol?ref_src=twsrc%5Etfw">@NatImmunol</a> compared <a href="https://twitter.com/hashtag/Treg?src=hash&ref_src=twsrc%5Etfw">#Treg</a> differentiation potential of <a href="https://twitter.com/hashtag/CD25?src=hash&ref_src=twsrc%5Etfw">#CD25</a>+ versus Foxp3(low) precursors in the #<a href="https://twitter.com/hashtag/thymus?src=hash&ref_src=twsrc%5Etfw">#thymus</a>. <a href="https://t.co/rIFWqybNnm">https://t.co/rIFWqybNnm</a> <a href="https://t.co/9ibTGBeHF9">pic.twitter.com/9ibTGBeHF9</a></div>
— David Usharauli (@3DiMMUNE) <a href="https://twitter.com/3DiMMUNE/status/1087859313723564037?ref_src=twsrc%5Etfw">January 22, 2019</a></blockquote>
<script async="" charset="utf-8" src="https://platform.twitter.com/widgets.js"></script>
<br />
<div class="separator" style="clear: both; text-align: center;">
<a href="https://1.bp.blogspot.com/-FEguRGgMDXE/XEe0ICFOJ4I/AAAAAAAAEJY/CkJSeiis29cBCpDhpKeGpVwC_ePLK1bbACLcBGAs/s1600/Screenshot%2B%25281751%2529.png" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="624" data-original-width="582" height="320" src="https://1.bp.blogspot.com/-FEguRGgMDXE/XEe0ICFOJ4I/AAAAAAAAEJY/CkJSeiis29cBCpDhpKeGpVwC_ePLK1bbACLcBGAs/s320/Screenshot%2B%25281751%2529.png" width="298" /></a></div>
<blockquote class="twitter-tweet tw-align-center" data-lang="en">
<div dir="ltr" lang="en">
2. One interesting <a href="https://twitter.com/hashtag/difference?src=hash&ref_src=twsrc%5Etfw">#difference</a> between CD25+ vs. Foxp3(low) <a href="https://twitter.com/hashtag/precursors?src=hash&ref_src=twsrc%5Etfw">#precursors</a> was dependency on <a href="https://twitter.com/hashtag/IL4?src=hash&ref_src=twsrc%5Etfw">#IL4</a> <a href="https://twitter.com/hashtag/signaling?src=hash&ref_src=twsrc%5Etfw">#signaling</a> to generate Tregs only from Foxp3(low) precursors (both responded to IL-2). <a href="https://t.co/hNoLxVBfIP">pic.twitter.com/hNoLxVBfIP</a></div>
— David Usharauli (@3DiMMUNE) <a href="https://twitter.com/3DiMMUNE/status/1087859317859069952?ref_src=twsrc%5Etfw">January 22, 2019</a></blockquote>
<script async="" charset="utf-8" src="https://platform.twitter.com/widgets.js"></script>
<br />
<blockquote class="twitter-tweet tw-align-center" data-lang="en">
<div dir="ltr" lang="en">
in summary, two types of thymic precursors can generate Tregs. Since their <a href="https://twitter.com/hashtag/TCR?src=hash&ref_src=twsrc%5Etfw">#TCR</a> did not overlap with each other but both of them overlapped with mature <a href="https://twitter.com/hashtag/Foxp3?src=hash&ref_src=twsrc%5Etfw">#Foxp3</a>+ <a href="https://twitter.com/hashtag/Tregs?src=hash&ref_src=twsrc%5Etfw">#Tregs</a> it suggests certain <a href="https://twitter.com/hashtag/functional?src=hash&ref_src=twsrc%5Etfw">#functional</a> bifurcation considering differences in protection against tissue <a href="https://twitter.com/hashtag/inflammation?src=hash&ref_src=twsrc%5Etfw">#inflammation</a>.</div>
— David Usharauli (@3DiMMUNE) <a href="https://twitter.com/3DiMMUNE/status/1087859321814298625?ref_src=twsrc%5Etfw">January 22, 2019</a></blockquote>
<script async="" charset="utf-8" src="https://platform.twitter.com/widgets.js"></script>
David Usharaulihttp://www.blogger.com/profile/02668672470276307921noreply@blogger.com0tag:blogger.com,1999:blog-6821948329541212415.post-19895420717077202282019-01-16T19:16:00.001-05:002019-01-16T19:16:07.187-05:00Foxp3+ Tregs suppress other T cells by stripping DCs of specific antigen/MHC complexes <blockquote class="twitter-tweet tw-align-center" data-lang="en"><p lang="en" dir="ltr">Ag-specific or not Ag-specific, that is [maybe was] question for <a href="https://twitter.com/hashtag/Foxp3?src=hash&ref_src=twsrc%5Etfw">#Foxp3</a>+ Tregs mechanism of action. New paper in <a href="https://twitter.com/NatImmunol?ref_src=twsrc%5Etfw">@NatImmunol</a> from <a href="https://twitter.com/hashtag/Shevach?src=hash&ref_src=twsrc%5Etfw">#Shevach</a>'s lab <a href="https://twitter.com/NIH?ref_src=twsrc%5Etfw">@NIH</a> says definitely antigen-specific. Lets dive in. BTW, ~20 years ago his lab developed assays that showed it was non-specific 🤫</p>— David Usharauli (@3DiMMUNE) <a href="https://twitter.com/3DiMMUNE/status/1085685514869620736?ref_src=twsrc%5Etfw">January 16, 2019</a></blockquote>
<script async src="https://platform.twitter.com/widgets.js" charset="utf-8"></script>
<blockquote class="twitter-tweet tw-align-center" data-conversation="none" data-lang="en"><p lang="en" dir="ltr">Now his lab made U-turn and concluded that <a href="https://twitter.com/hashtag/suppression?src=hash&ref_src=twsrc%5Etfw">#suppression</a> by <a href="https://twitter.com/hashtag/Tregs?src=hash&ref_src=twsrc%5Etfw">#Tregs</a> is actually <a href="https://twitter.com/hashtag/antigen?src=hash&ref_src=twsrc%5Etfw">#antigen</a>-specific and difference between now and then comes down to in <a href="https://twitter.com/hashtag/vitro?src=hash&ref_src=twsrc%5Etfw">#vitro</a> versus in <a href="https://twitter.com/hashtag/vivo?src=hash&ref_src=twsrc%5Etfw">#vivo</a> assays 🤔</p>— David Usharauli (@3DiMMUNE) <a href="https://twitter.com/3DiMMUNE/status/1085685515511308289?ref_src=twsrc%5Etfw">January 16, 2019</a></blockquote>
<script async src="https://platform.twitter.com/widgets.js" charset="utf-8"></script>
<blockquote class="twitter-tweet tw-align-center" data-lang="en"><p lang="en" dir="ltr">2. This <a href="https://twitter.com/hashtag/antigen?src=hash&ref_src=twsrc%5Etfw">#antigen</a>-specific <a href="https://twitter.com/hashtag/suppression?src=hash&ref_src=twsrc%5Etfw">#suppression</a> was still active when antigen-specific dendrtic cells were removed from Treg co-culture (1st culture) and exposed to T cells (2nd culture). <a href="https://t.co/dj1pzDuNNv">pic.twitter.com/dj1pzDuNNv</a></p>— David Usharauli (@3DiMMUNE) <a href="https://twitter.com/3DiMMUNE/status/1085685517927231488?ref_src=twsrc%5Etfw">January 16, 2019</a></blockquote>
<script async src="https://platform.twitter.com/widgets.js" charset="utf-8"></script>
<blockquote class="twitter-tweet tw-align-center" data-lang="en"><p lang="en" dir="ltr">So, from now on if someone asks you how Treg suppress other T cells don't hesitate to reply "antigen-specific manner", add Ethan Shevach said so and no one will argue with you. got it 🤨 <a href="https://t.co/I4pAYIIGy1">https://t.co/I4pAYIIGy1</a></p>— David Usharauli (@3DiMMUNE) <a href="https://twitter.com/3DiMMUNE/status/1085685521609904128?ref_src=twsrc%5Etfw">January 16, 2019</a></blockquote>
<script async src="https://platform.twitter.com/widgets.js" charset="utf-8"></script>
David Usharaulihttp://www.blogger.com/profile/02668672470276307921noreply@blogger.com0tag:blogger.com,1999:blog-6821948329541212415.post-4527747223127255812019-01-14T19:35:00.000-05:002019-01-14T19:35:21.044-05:00Tumor infiltrating Foxp3+ Tregs recognize synthesized but not naturally available cancer neoantigens
<blockquote class="twitter-tweet tw-align-center" data-lang="en"><p lang="en" dir="ltr">In new paper in <a href="https://twitter.com/SciImmunology?ref_src=twsrc%5Etfw">@SciImmunology</a>, Steven Rosenberg's group from <a href="https://twitter.com/NIH?ref_src=twsrc%5Etfw">@NIH</a> asks why are <a href="https://twitter.com/hashtag/Tregs?src=hash&ref_src=twsrc%5Etfw">#Tregs</a> accumulate in tumor tissues and if it has something to do with <a href="https://twitter.com/hashtag/cancer?src=hash&ref_src=twsrc%5Etfw">#cancer</a> <a href="https://twitter.com/hashtag/antigen?src=hash&ref_src=twsrc%5Etfw">#antigen</a> recognition. But how to study <a href="https://twitter.com/hashtag/Foxp3?src=hash&ref_src=twsrc%5Etfw">#Foxp3</a>+ Tregs in humans? No reliable surface marker exist yet.</p>— David Usharauli (@3DiMMUNE) <a href="https://twitter.com/3DiMMUNE/status/1084958725591453696?ref_src=twsrc%5Etfw">January 14, 2019</a></blockquote>
<script async src="https://platform.twitter.com/widgets.js" charset="utf-8"></script>
<blockquote class="twitter-tweet tw-align-center" data-conversation="none" data-lang="en"><p lang="en" dir="ltr">1. First, they sorted fix/perm T cells from <a href="https://twitter.com/hashtag/tumor?src=hash&ref_src=twsrc%5Etfw">#tumor</a> samples based on Foxp3+ expression to separate <a href="https://twitter.com/hashtag/Tregs?src=hash&ref_src=twsrc%5Etfw">#Tregs</a> from non-Tregs and sent the sorted samples to <a href="https://twitter.com/AdaptiveBiotech?ref_src=twsrc%5Etfw">@AdaptiveBiotech</a> (this is what all do now days looks like) for deep <a href="https://twitter.com/hashtag/TCR?src=hash&ref_src=twsrc%5Etfw">#TCR</a> <a href="https://twitter.com/hashtag/sequencing?src=hash&ref_src=twsrc%5Etfw">#sequencing</a> and alpha/beta TCR <a href="https://twitter.com/hashtag/pairing?src=hash&ref_src=twsrc%5Etfw">#pairing</a>.</p>— David Usharauli (@3DiMMUNE) <a href="https://twitter.com/3DiMMUNE/status/1084958726304481286?ref_src=twsrc%5Etfw">January 14, 2019</a></blockquote>
<script async src="https://platform.twitter.com/widgets.js" charset="utf-8"></script>
<blockquote class="twitter-tweet tw-align-center" data-conversation="none" data-lang="en"><p lang="en" dir="ltr">2. They found differences between Treg-TCRs usage and non-Treg TCR usage. OK. Then what? <a href="https://twitter.com/hashtag/Sequencing?src=hash&ref_src=twsrc%5Etfw">#Sequencing</a> or even TCR pairing by itself have no value unless one knows what these <a href="https://twitter.com/hashtag/TCR?src=hash&ref_src=twsrc%5Etfw">#TCR</a> recognize. Many labs don't even bother to do anything about it, but <a href="https://twitter.com/hashtag/Rosenberg?src=hash&ref_src=twsrc%5Etfw">#Rosenberg</a>'s people did.</p>— David Usharauli (@3DiMMUNE) <a href="https://twitter.com/3DiMMUNE/status/1084958727118245888?ref_src=twsrc%5Etfw">January 14, 2019</a></blockquote>
<script async src="https://platform.twitter.com/widgets.js" charset="utf-8"></script>
<blockquote class="twitter-tweet tw-align-center" data-conversation="none" data-lang="en"><p lang="en" dir="ltr">3. To do it, they took top <a href="https://twitter.com/hashtag/Foxp3?src=hash&ref_src=twsrc%5Etfw">#Foxp3</a>+ <a href="https://twitter.com/hashtag/Treg?src=hash&ref_src=twsrc%5Etfw">#Treg</a> TCRs pairs and <a href="https://twitter.com/hashtag/transfected?src=hash&ref_src=twsrc%5Etfw">#transfected</a> them individually into <a href="https://twitter.com/hashtag/autologous?src=hash&ref_src=twsrc%5Etfw">#autologous</a> T cells and tested their <a href="https://twitter.com/hashtag/reactivity?src=hash&ref_src=twsrc%5Etfw">#reactivity</a> to autologous tumor samples. Some <a href="https://twitter.com/hashtag/TCR?src=hash&ref_src=twsrc%5Etfw">#TCR</a> specifically recognized something in autologous tumor samples. They thought it must <a href="https://twitter.com/hashtag/antigen?src=hash&ref_src=twsrc%5Etfw">#antigen</a>. <a href="https://t.co/fbj8esBJSq">pic.twitter.com/fbj8esBJSq</a></p>— David Usharauli (@3DiMMUNE) <a href="https://twitter.com/3DiMMUNE/status/1084958727801847808?ref_src=twsrc%5Etfw">January 14, 2019</a></blockquote>
<script async src="https://platform.twitter.com/widgets.js" charset="utf-8"></script>
<blockquote class="twitter-tweet tw-align-center" data-conversation="none" data-lang="en"><p lang="en" dir="ltr">4. To identify antigen recognized by Treg TCRs, they used whole-<a href="https://twitter.com/hashtag/exome?src=hash&ref_src=twsrc%5Etfw">#exome</a> and RNA sequencing (RNA-seq) to detect somatic mutations and make mutant peptide pool. Indeed one Treg TCR from one patient and another Treg TCR from another patient recognized mutant <a href="https://twitter.com/hashtag/annexin?src=hash&ref_src=twsrc%5Etfw">#annexin</a> A1 and <a href="https://twitter.com/hashtag/CCL5?src=hash&ref_src=twsrc%5Etfw">#CCL5</a>. <a href="https://t.co/FRiibvwYTX">pic.twitter.com/FRiibvwYTX</a></p>— David Usharauli (@3DiMMUNE) <a href="https://twitter.com/3DiMMUNE/status/1084958730221957127?ref_src=twsrc%5Etfw">January 14, 2019</a></blockquote>
<script async src="https://platform.twitter.com/widgets.js" charset="utf-8"></script>
<blockquote class="twitter-tweet tw-align-center" data-conversation="none" data-lang="en"><p lang="en" dir="ltr">5. But here is the twist. None of these <a href="https://twitter.com/hashtag/Treg?src=hash&ref_src=twsrc%5Etfw">#Treg</a> <a href="https://twitter.com/hashtag/TCRs?src=hash&ref_src=twsrc%5Etfw">#TCRs</a> recognized autologous tumor samples. Interestingly, for <a href="https://twitter.com/hashtag/annexin?src=hash&ref_src=twsrc%5Etfw">#annexin</a> A1 the authors suggested its expression was too low in tumor samples and for <a href="https://twitter.com/hashtag/CCL5?src=hash&ref_src=twsrc%5Etfw">#CCL5</a> they found that tumor cells actually do not express CCL5 at <a href="https://twitter.com/hashtag/RNA?src=hash&ref_src=twsrc%5Etfw">#RNA</a> level.</p>— David Usharauli (@3DiMMUNE) <a href="https://twitter.com/3DiMMUNE/status/1084958732600205313?ref_src=twsrc%5Etfw">January 14, 2019</a></blockquote>
<script async src="https://platform.twitter.com/widgets.js" charset="utf-8"></script>
<blockquote class="twitter-tweet tw-align-center" data-conversation="none" data-lang="en">
<div dir="ltr" lang="en">
Basically, Treg TCR could recognize lab <a href="https://twitter.com/hashtag/synthesized?src=hash&ref_src=twsrc%5Etfw">#synthesized</a> <a href="https://twitter.com/hashtag/mutant?src=hash&ref_src=twsrc%5Etfw">#mutant</a> peptides from patient samples but not natural <a href="https://twitter.com/hashtag/tumor?src=hash&ref_src=twsrc%5Etfw">#tumor</a> cells. So, the authors ended up back in square one. <a href="https://twitter.com/hashtag/Tregs?src=hash&ref_src=twsrc%5Etfw">#Tregs</a> go to tumor tissues but the methods we have right now does not allow us to know what Ag they see it there.</div>
— David Usharauli (@3DiMMUNE) <a href="https://twitter.com/3DiMMUNE/status/1084958733262880775?ref_src=twsrc%5Etfw">January 14, 2019</a></blockquote>
<script async="" charset="utf-8" src="https://platform.twitter.com/widgets.js"></script>
David Usharaulihttp://www.blogger.com/profile/02668672470276307921noreply@blogger.com0