Too good to be to true

Currently, Foxp3+ CD4 T cells, also known as regulatory T cells (Tregs), are most studied and still least understood T cell subset. Why is that? The main challenge to Tregs/suppressor concept is that they do not fit in any mainstream theoretical framework of immune system organization. In absence of such working model, translation of basic Tregs research into clinical practice will look as sporadic efforts with no real progress and consensus.

If you are interesting to know more about Tregs, I will recommend reading following article published in journal Nature few weeks ago. This study by Michael Rosenblum et al. (1), exactly represents that confusion typical to Tregs research. First, this is a fairly simple study and we may applaud Nature for taking step to publish a research paper that does not include highly expensive (in many cases completely irrelevant or useless) experimental methods. Actually I see some pattern in this direction from Nature's editorial board. Nature started to publish simple papers (the most recent example of this kind is a research article about dendritic cells and lymph node-specific high endothelial venules). However, simplicity is not the same as significance or relevance.

In this new article by Michael Rosenblum et al., the authors created mice that will express OVA antigen in the skin only upon treatment with a doxycycline and crossed them to the mice transgenic for OVA-specific T cell. In absence of doxycycline, this modified mice have healthy skin, and harbor substantial population of OVA-specific Tregs (due to doxycycline-independent thymic expression of OVA). Within 5-10 days upon doxycycline treatment, the skin becomes highly inflamed due to OVA-specific T cell effector infiltration. However, within 40-60 days skin inflammation is completely resolved. How? The authors suggested that it has to do with Tregs, because Tregs depletion led to more severe skin inflammation. The problem is that even in condition of Tregs depletion, the skin inflammation is still resolved and almost within the same time frame as in presence of Tregs (Fig 2a, e, g). In general, Tregs depletion with anti-CD25 antibody may not eliminate all Tregs, so this particular experiments are not optimal approaches. This leave open the main question what is the role of Tregs in this process. In Fig. 4E, f, the authors showed that when expression of OVA is turned off for 20-30 days and then turned on again, skin inflammation that developed 2^nd time is less severe and is resolved at faster rate compared to initial skin inflammation in the same mice. The authors showed that after resolution of initial skin inflammation, there were more Tregs retained in the skin and these Tregs were more potent in suppressing naïve T cells proliferation. The authors conclusion is that tissue (skin) maintains memory Tregs specific to initial antigen and their presence is required to resolve skin inflammation.

Essentially, the authors idea is that similar to effector T cells, Tregs also undergo the same phases of a typical immune response: activation, expansion, memory differentiation. In my opinion, the data to support this claim are weak. First, Tregs depletion should have been done with Foxp3-DTR mice to selectively deplete Foxp3+ T cells and second, no data is provided to show that initial OVA expression and inflammation does not select for skin epithelial cells expressing less of OVA that may have explained reduced inflammation upon re-expression of OVA in the skin.

David

1. http://www.nature.com/nature/journal/vaop/ncurrent/full/nature10664.html

does stress induce allergy?

Here is another example of what I call “right paper wrong journal”. This time we should thank journal Science for not disappointing us.

Type I allergic reaction is characterized by production of antigen-specific IgE. Upon re-encounter with the corresponding antigen, IgE molecules engage receptors on mast cells, eosinophils or basophils that results in release of histamine or other active enzymes. These substances induce smooth muscle contraction, capillary permeability, mucus production, leading to clinical signs of asthma, skin rash, itching, mucosal swelling. It seems that IgE responses are bad. So why we have it? In general, evolutionary explanation for IgE response was its role in defense against intestinal parasites (worms). However, today very diverse set of antigens (for example, some food) could induce IgE response. How they do it is not at all clear.

The study I was referring to earlier was recently published in journal Science (1). This paper by Jessica Strid et al., examined an effect of innate T cell activation on IgE response. This innate T cells, called γδ T cells express NKG2D molecules that recognize tissue stress-induced ligand, Rae-1. By analyzing mice where expression of RAE-1 could be manipulated (on/off), the author showed that if skin application of nominal (neutral) antigen, OVA, was coincided with NKG2D-Rae-1 interaction, this led to allergy-prone OVA-specific IL-13 and IgE production from adaptive immune system. They showed that the imprinting of this allergy-prone responses were reduced in γδ T cell-deficient mice, NKG2D-deficient mice or in mice deficient in only subset of γδ T cell residing in mouse skin. The authors concluded that tissue-stressed induced innate T cell activation promotes allergy-prone IgE adaptive immune response.

This paper is very good paper for journal of immunology, for example. It's main strength is the idea that links environmental toxins (chemical pollutants) to allergy development. It's fundamental weakness is its reliance on IgE or IL-13 production as a sole signature of allergic response. They do not provide any data that would suggest that upon antigen re-encounter, this increase in OVA-specific IgE production, as observed in this study, could induce any clinically relevant sign of allergy. Shortly, this study lacks "science-level" relevance.

I personally find it difficult to believe that tissue-surveillance program through NKG2D-Rae-1 interaction should lead to IgE response. After all, tissue-surveillance program was originally thought to be primarily directed against tumors, where protection is mediated  through IFN-γ pathway, not IL-13/IgE pathway.

David     

1. http://www.sciencemag.org/content/334/6060/1293.short

trust but verify

Innate immune system detects the pathogen invasion and alerts adaptive immune system to its presence. However it is not always clear whether adaptive immune system should be alerted to the presence of any dose of pathogenic inoculum. May be innate immune system can handle low dose of pathogenic inoculum alone? However, what if innate immune system tries to handle the pathogen alone, fails doing it and alerts adaptive immune system too late when pathogenic onoculum become too large? The exact balance that will increase protective immunity and at the same time reduce tissue damage will depend on many variables, many of them still unknown.

If you are interested to know more about the complex interaction between innate and adaptive immune systems, I will recommend reading the following research article published in Nature Immunology a few weeks ago. In this study by Nadine Honke et al. (1), the authors first showed that in mice, intravenously injected (i.v.) vesicular stomatitis virus (VSV) is rapidly captured and cleared from the bloodstream by tissue macrophages. However, interestingly, the authors could detect the presence of live virus only in spleen tissue. Specifically, live virus was maintained in specialized macrophages called marginal zone macrophage that are identified by staining for CD169 marker. In contract, live virus could be recovered from all tissue examined from wild-type mice depleted of macrophages or from mice deficient in IFN-α receptor. These results suggested that CD169+ macrophages have some unique properties that allow them to maintain live virus in wild-type mice. The authors showed it may be related to higher expression of IFN-α signaling inhibitor Usp18 in CD169+ macrophages as compared to other tissue macrophages, for example, F4/80+ macrophages. Indeed, expression of VSV was absent in CD169+ macrophages from Usp-18 deficient mice. In other words, CD169+ macrophages “intentionally” inhibit IFN-α signaling in order to maintain live virus. Why is that? The authors explained this puzzle by observation that VSV-specific T cell and IgG response were reduced in Usp-18 deficient mice. Moreover, Usp-18 deficient mice became very susceptible to i.v. Injected VSV. Usp-18 deficient mice harbor far less live virus in the spleen at early time point post infection (at 7h) and harbor far more live virus in brain at late time point post infection (at 7 days). In addition, the authors showed that live virus primed VSV-specific adaptive immune response more efficiently compared to inactivated VSV. The authors concluded that “deliberate” maintenance of replication-competent virus in CD169+ macrophages gives enough time or antigenic material for efficient priming of protective adaptive immune response, while inactive virus is far inferior in providing signals necessary for efficient priming of protective adaptive immune response.

However, there are several holes in the story. The authors did not show results whether (1) VSV-specific T cells response was reduced in mice depleted of CD169+ macrophages or (2) whether mice depleted of CD169+ macrophages became more susceptible to VSV. Without these controls the whole concept of the paper will be misleading.

David

1. http://www.nature.com/ni/journal/vaop/ncurrent/full/ni.2169.html

gut instinct is depressing

does Immune system has any role besides protecting the body from infections? In my opinion, the answer is probably NO. Once in a while, however, you may find a study claiming otherwise (for example, study claiming that adaptive immune system improves neuron function and memory (1). These type of studies are usually based on observations derived from mice with a defective immune system (missing one or several components of immune system). The main challenge to these type of conclusions is the fact that because normal body harbors myriad varieties of microbes (in the gut, skin, oral cavity, etc.), then even a simple alteration of immune system may indirectly affect other tissue's function though its direct (missing)impact on microbiota. In order to properly address the involvement of immune system in other tissues function experiment should be carried out in the absence of microbiota, for example, in germ-free mice.

If you interested to know more whether immune system could affect other tissue's function and also to illustrate my point, I will recommend reading the following paper that appeared recently in Nature Medicine. This study, by Shulzhenko N and Morgun A et al., looked at intestinal tissue function in the absence of B cells (2). Using several lines of B cell or immunoglobulin (Ig) knock-out (KO) mice and gene microarray analysis, they found that there was very similar changes of intestinal tissue in mice missing B cells or IgA compared to wild type littermates (Fig 2c). In general, genes involved in defense were up-regulated and genes involved in metabolism were down-regulated in B cell KO mice compared to wild type littermates. This may have implied that B cells modulate intestine tissue function. However, to rule out indirect effect of microbiota, they carried out the same experiment in germ-free B cell KO or germ-free wild type mice. As expected, the difference in gene expression of intestinal tissue between B cell KO and wild type mice disappeared on germ-free background (Fig 3c,d). Of note, similar down-regulation of intestinal tissue metabolism occurred in both B cell KO and RAG KO mice (that lacks T cells as well) but it did not occur on germ-free background. These data suggested that improper activation of adaptive immune system in the absence of B cells were not responsible for down-regulation of intestinal metabolism and that microbiota was involved. Because gene expression profile of B cell KO mice was very similar to gene expression profile of intestinal tissue derived from mice with intestinal epithelial-specific deletion of GATA4 transcription factor, the authors concluded that altered microbiota (as a result of lack of B cells/IgA) directly affected intestine tissue metabolism. They also supported this conclusion by profiling gene expression of isolated intestinal epithelial cells from B cell KO mice and using mouse intestinal cell line treated with different inflammatory stimuli. In my opinion, the caveat of this interpretation is the fact that (a) gut tissue contains diverse set of innate immune cells (for example, lymphoid-tissue inducer-like cells) that could have affected gut metabolism and (b) intestinal epithelial cells isolated from B cell KO mice might had already received signals from these innate immune system (and not directly from microbiota) (in Fig. 5c). In my opinion, the better way to support their conclusion would have been to isolate intestinal epithelial cells from germ-free mice and treat them with different microbes or their components.

Overall, this study is one of best example of how proper experimental approach reveals the hidden effect of microbiota on intestinal tissue in the absence of one component of immune system, in this case the absence of B cells (and IgA).

David

1. http://www.nature.com/neuro/journal/v9/n2/full/nn1629.html

2. http://www.nature.com/nm/journal/vaop/ncurrent/full/nm.2505.html

A freak of Nature

Today I am going to introduce a new discussion topic I call “right paper wrong journal”.

Scientist are looking for two things in the journal editor: integrity and good judgment. In many occasions, we have a situation when a publication of a particular paper represents editor's less than a good judgment. By judgment here I mean a relevance and a value paper brings to the journal readers. Paper can be well designed and properly done but it may not make a significant contribution for the knowledge advancement. 

Here is the example of such paper that was recently published in Nature (Nature is widely regarded a the world's most prestigious science journal). In this paper by Christine Moussion and Jean-Philippe Girard (1), the authors showed that in vivo a proper maintenance of lymph node (LN)-specific endothelial cells, called high endothelial venules (HEV), requires their interaction with dendritic cells through lymphotoxin-β receptor. As a functional outcome, the authors showed that in the absence of dendritic cells LNs had reduced cellularity due to a reduced capacity of lymphocytes to adhere to the HEV and enter the LN. However, no data is provided how this changes would have affected any meaningful immunological response. Any way, absence of dendritic cells by itself (independent of HEV functionality) will make an initiation of antigen-specific immune response almost impossible. Is there any reason why this paper could have not be published in Journal of Immunology?

David

(1) http://www.nature.com/nature/journal/vaop/ncurrent/full/nature10540.html

memory CD8 T cell Id(3)'d

The hallmark of an adaptive immune system is to respond more robustly when challenged again with the same antigen. It is called a memory response. CD8 T cells are the best studied model of antigen-specific CD8 T cell population expansion and contraction during antigenic challenge. Effector CD8 T cells that survive contraction phase form memory pool. It is estimated that only around 1-10% of a peak response CD8 T cells survive the memory bottleneck. Understanding the molecular mechanisms that allow a particular CD8 T cell to survive contraction phase will help to design better vaccination strategy. Many factors have been described that correlates (control) with memory CD8 T cells formation (for example, IL-7Ralpha or IL-2Ralpha expression). However so far no one came up with a clear model that could explain what controls the controllers. In my opinion, the answer will be found in the T cell receptor (TCR) specificity and in precise understanding how strength of signaling is translated into individual CD8 T cell fate.

If you interested to know more about mechanisms of CD8 T cell memory formation, I would recommend reading the following two papers recently published in Nature Immunology. Both papers, one by Cliff Yang et al. (1), and another by Yun Ji et al.(2), showed that the expression of transcription factor Id3 is necessary for memory CD8 T cells formation. Following data are critical for an analysis: in paper by Cliff Yang et al., Fig. 1e shows that expression level of Id3 is higher when increasing number of CD8 T cells are transferred. This may imply that Id3 is maintained more easily in CD8 T cells that receives minimal stimulation. Fig. 2B shows that Id3high CD8 T cells produce more IL-2 compared Id3low CD8 T cells. Fig. 3E shows that Id3high CD8 T cells are maintained in higher numbers upon adoptive transfer compared to Id3low CD8 T cells. Fig. 5A shows that Id3-deficient transgenic CD8 T cells (on wt background) are impaired in survival after viral infection compared to Id3-sufficient OT-I cells (3-fold reduction at day 60). In paper by Yun Ji et al., however, survival disadvantage of Id3-deficient transgenic CD8 T cells (on RAG KO background) is more pronounced compared to Id3-sufficient transgenic CD8 T cells. This may imply that TCR affinity (OT-I vs. pmel-1 or wt vs. RAG KO background) determines the absolute need for Id3 for memory formation.

David Usharauli         

microbiota greenlights brain inflammation

For the past few years published literature in immunology became enriched in studies related to commensial microbiota found mainly in mammalian gut. There is one simple explanation for this renewed interest in commensial microbiota: discovery and characterization of Toll-like receptors (TLRs) in late 90's (recognized by Nobel prize in Physiology or Medicine 2011). TLRs opened the door to study microbiota-host interaction at molecular level and made it easy to explain experimental observations mechanistically. In general, commensial microbiota could influence immune system in two ways: first, it could provide the antigenic material for adaptive immune system activation (T or B cells activation) and second, it could provide TLR ligands for innate immune system activation.

If you are interested to know more about commensial microbiota-host interaction, I will recommend to read the following article recently published in Nature. This study by Kerstin Berer et al. (1), examined the effect of commensial microbiota on the development of brain autoimmune disease in SJL/J TCR transgenic mice. In this mouse, if housed in a regular laboratory mouse facility, brain inflammation occurs spontaneously and is mediated by combined effect of MOG-specific T cells and B cells. However, according to this study, this type of brain inflammation does not occur in this mouse made germ-free (in sterile, microbiota free state). The disease development in this mouse require the presence of MOG protein because in its absence there is no brain inflammation irrespective of presence of absence of commensial microbiota. This results suggest that microbiota provide antigen-independent effect leading to stimulation of MOG-specifc T and B cells. However, how microbiota does it is not clear. The authors showed that there is reduction of IL-17 producing T cells in the gut of germ-free mouse. However, the authors provide no direct evidence whether IL-17-producing T cells play any role in disease development.

David Usharauli                  

missing link gets 11 points

Innate immune system detects the presence of structural components of microbes/viruses/fungi and alerts the adaptive immune system. Toll-like receptors are so far the most studied class of these innate sensors (recognized with Nobel Prize in Physiology or Medicine 2011). However, there is another class of innate sensors represented by cytosolic NOD-like receptors (NLRs)/caspase-1 pathway. This class of sensors form so called inflammasome complexes that detect virulence factors derived from microbes/viruses/fungi. Activation of caspase-1 cleaves pro-IL-1beta into active IL-1beta, releases active IL-1alpha and causes cell death called pyroptosis. Earlier studies have shown that caspase-1 deficient mice are resistant to endotoxin-induced septic shock, a mouse model of sepsis.

If you are interested to know more about inflammasome, I will recommend to read the following article published in Nature. I personally think that this article is the best immunology paper published so far this year. This study by Nobuhiko Kayagaki et al. (1), examined the activation of inflammasome by cholera toxin component B (CTB). While LPS-primed macrophages from B6 and other commonly used mice strains responded to CTB by producing active IL-1beta, LPS-primed macrophages from 129S6 strain failed to respond to CTB. It turned out that 129S6 mouse has a mutation in caspase-11 gene. By creating caspase-11 deficient B6 mice the authors confirmed that the failure of 129S6 mice to respond to CTB was indeed related to caspase-11 mutation. In addition to CTB, both caspase-11 deficient B6 mouse and 129S6 failed to release IL-1beta (via caspase-1 pathway) in response to E. coli, C. rodentium and V. cholerae, but responded to ATP, LLO, MSU, nigericin and others. Failure to activate this caspase-11-dependent, but caspase-1-independent non-canonical inflammasome pathway resulted in reduced IL-1alpha release and reduced cell death (pyroptosis). By analyzing available caspase-1 deficient mice, the authors showed that they were deficient in caspase-11 as well, because they were derived from 129 mouse ES cells. These results raised the question about interpretation of the data derived from caspase-1 deficient mice experiments. By creating caspase-1 KO/caspase-11 transgenic mouse, the authors showed finally that endotoxin-induced septic shock was mediated by caspase 11, not caspase 1, as originally thought. How caspase-11 mediates LPS toxicity is not clear. It could be related to pyroptosis.

This serendipitous discovery will lead to the better understanding of sepsis immuno-pathology and ultimately will lead to improvement in treatment outcome.

David Usharauli     

CD8 T cells: too selfish to share IL-2

CD8 T cells play a pivotal role in body's defense against viral infections. While it is relatively easy to see activation of CD8 T cells against a real infectious virus, nominal, non-replicative antigens (used in many vaccines) have a hard time to mimic it. In general, CD4 T cell help and antigen presentation by dendritic cell (DC) are required to activate CD8 T cell. In 1998, three articles published back to back in Nature showed that one mechanism of CD4 T cell help was through CD40L-triggered DC (called licensing). Later, another mechanism has been discovered: help through IL-2 signaling in CD8 T cells. Both mechanisms, however, created some confusion in scientific community. The point is that both CD40L as well as IL-2 can be expressed by all three types of cell involved in CD8 T cell activation: CD4 helper cell, DC and CD8 T cell. The debate then and now is about what kind of cell (CD4, DC, CD8) has to express CD40L or IL-2 to provide biologically significant help for CD8 T cell activation.

If you are interested to know more about “help” signal to CD8 T cell, I will recommend to read the new article from Steve Schoenberger's Lab (one of the author of the original 1998 paper) published recently in Nature Immunology. In the study by Sonia Feau et al (1), the author showed that CD8 T cell activation or it's memory formation was comparable whether CD4 T cells could express IL-2 or not. CD40L blockade, however, inhibited CD8 T cell response. No data are provided, however, to understand whether CD40L expression on CD4 T cell (or other cell types) was involved here. The critical data are in Fig. 3 and 4. In Figure 3, using infectious virus, the author showed that IL-2-deficient CD8 T cells expanded less compare to IL-2-sufficient CD8 T cells. Interestingly, IL-2-deficient CD8 T cells behaved exactly as if IL-2-sufficient CD8 T cells (in mouse)-depleted of CD4 T cells. Another critical point is that in CD4 T cell-depleted host, the expansion of endogenous, wild-type CD8 T cells was more reduced in the presence of IL-2-deficient donor CD8 T cells compared to IL-2-sufficient donor CD8s (Fig. 3c). This is in contrast to Fig. 4C, where the reduction is equivalent (here the antigen is non-infectious in nature).

CD8 T cells do produce IL-2 but its biological role was dismissed or ignored until now. After reading this articles, one question comes to my mind is if CD8 T cell can produce IL-2 and can express CD40L, why there is a need for CD4 T cell help?

David Usharauli        

Th17: thymus keeps it natural

IL-17-producing T cells, called T helper 17 cells (Th17) have been one of the main focus of immunological research since their discovery in 2006. Th17 cells gained such popularity for wrong reason: their involvement in bodies own tissue destruction or commonly known as autoimmune diseases. Very little is known about Th17 role in protection against infection (so far, we know that they contribute primarily in defense against fungi and extracellular bacteria). One peculiar feature of Th17 cells was the discovery that TGF-beta (in combination with IL-6 or IL-21) was needed for their generation, in in vitro assays, at least. This was interesting because TGF-beta is needed for the generation of Foxp3+ regulatory T cells (Tregs). According to current interpretation, the balance between Th17 and Tregs determines autoimmunity versus tolerance outcome.

If you are interesting to know more about Th17 cells, I will recommend reading the following paper recently published in Journal of Experimental Medicine. In this study (1), Kim et al, made several noteworthy observations: first, they showed that thymus from naive mice contains population of CD4 T cells expressing IL-17. Second, this thymic-derived Th17 cells are enriched in one particular T cell receptor gene, called V beta 3. Third, this Th17 cells need to interact with MHC class II molecules expressed on radioresistant thymic medullary epithelial cells to develop. Fourth, reduced T cell receptor signaling (Y145F mutation) favor their development. Fifth, the same Y145F mutation, however, prevented proper development/differentiation of peripheral, gut-associated Th17 cells.

It seems that paper represents the mix of two independent projects. However, the authors conclusions (and title of the paper) are mainly focused on results from only one project, namely, that (based on Y145F mutation) there are two, non-overlapping Th17 populations, one thymic-derived, called natural Th17 and another peripherally-converted.

David Usharauli

IL-6: one more time, please ?!

Chronic infections represent a special challenge to the adaptive immune system. It would not be an exaggeration to say that essentially what we know about how an adaptive immune system normally functions is entirely based on research or clinical observation related to the acute infections. Chronic infection develops in situations when adaptive immune system is not capable of complete or near complete elimination of invader-pathogen. In this scenario, invader-pathogen persists long-term, slowly spreading, infecting healthy cells. At this point adaptive immune system faces a difficult choice: if it kills all infected cells then the tissue and body will not survive because this will cause too much damage (so called immune pathology). Only alternative solution for adaptive immune system (to T and B cells) is to switch to the “damage-control” mode, where the focus will be containment, not elimination. This will require new pathway of effector differentiation that causes minimal damage to the infected tissues.

If you are interested to know what kind of modifications are happening to adaptive immune system during chronic infections, I recommend to read the following article recently published in Science (1). In this paper by James Harker et al, the focus is on the mouse model of chronic viral infection, specifically LCMV clone 13. The first (and in my opinion only) interesting observation they made was how IL-6 expression changes during clone 13 infection. Unlike acute infection, clone 13 produces two peaks of IL-6: early (at day 1-3) and late (at day 25). This late peak of IL-6 is primarily derived from irradiation-resistant follicular dendritic cells (FDCs). The authors do not go beyond this simple observation to explain how this is happening. Furthermore, for some reason, they are totally neglecting to discuss another cytokine, G-CSF that similar to IL-6 also had biphasic expression and may play independent role in protection during chronic infection. The rest of the article is mainly supporting data (more or less already known), for example, showing how IL-6 influences T follicular helper cell development, that in turn affects virus-specific antibody production level and its affinity (while earlier studies mainly ignored the role of B cells or antibodies played during LCMV infection, the more recent research clearly shows that at least for clone 13 infection antibody-dependent protection is essential (2).

Such prominent role of IL-6 in protection against chronic infection as this article shows is supported by other independent observation. For examples, an article published in Cell showed that IL-7, another cytokine, has protective effect during clone 13 infection and this effect was dependent on IL-6 (3).

David Usharauli

blind love: neuro-immune chemistry

Immune and nervous systems share two unique characteristics: (a) both systems undergo adaptive “education” to discriminate between self and nonself signals and (b) both systems have “memory” to it.

So far few research papers had been published that addressed the question how these two complex systems interact with each other. For example, one paper claimed that T cells can promote neuronal re-generation and hence contribute to the learning process (1). These study was based on evidence that T cell transfer into immunodeficient mice improved neuronal generation. In my opinion, this interpretation fails to take into account the fact that T cell transfer into immunodeficient mice affect not just brain function but for instance, gut permeability too. Why is it important? It is well known that endotoxin (LPS) level in the blood affects brain function. LPS level in the blood, in turn, is influenced by gut permeability, that in turn, is influenced by immune system status. T cell transfer into immunodeficient mice would allow differentiation of gut-homing T cells that may have reduced gut permeability thus indirectly affecting brain function.

If you are interested in neuro-immune research, then I will recommend to read the following two papers recently published in Science (2, 3).

1^st paper from Kevin Tracey's Lab provided the direct evidence that the presence of specialized, acetylcholine-secreting memory T cells were necessary and sufficient to relay signals from nervous system to the immune (2).

2^nd paper from Paul Kubes Lab showed that CD1d-deficient mice (that lack all NKT cells) were more susceptible to stroke-associated immunosuppression compared to wild-type mice (3). This immunosuppression could be prevented by stimulating NKT cells or blocking noradrenalin signaling in these cells because this protective effect of noradrenalin blockade was abolished in CD1d-deficient mice. It is of note that both NKT presence and simultaneous blockade of noradrenalin signaling in these cells was necessary for full protection. This is a kind of paradox. However, because there are two types of NKT cells in mice, there may be a simple explanation. So it will be interesting to compare CD1d-deficient mice to Jalpha18-deficient mice that lack only one type of NKT cells. In my opinion, NKT cells transfer into CD1d-deficient mice would have provided more direct evidence of protective role of this innate NKT cells.

David Usharauli

(1) http://www.nature.com/neuro/journal/v9/n2/full/nn1629.html

(2) http://www.sciencemag.org/content/early/2011/09/14/science.1209985.abstract

(3) http://www.sciencemag.org/content/early/2011/09/14/science.1210301.abstract

OX40/CD30 lay off Foxp3

 Since it's discovery in 2001, a transcription factor called Foxp3 has been recognized as a master regulator of autoimmune disease. It's total deficiency in CD4 T cells has such a profound effect that mouse that lacks it usually die of inflammatory multi-organ failure within 3 weeks of birth.

We don't know how exactly Foxp3+ CD4 T cells prevent autoimmunity. Currently, there is no mechanistic model that could satisfactorily explain their function. Even at the theory level, Foxp3+ T cell role is either totally ignored/dismissed (for example, in SNS model) or characterized as an immune class-specific effector/memory T cells (for example, in danger model). In short, the viable concept of negative regulation of immune system by antigen-specific Foxp3+ CD4 T cells is yet to come.

If you are interested in Foxp3+ T cell biology, I recommend reading a new study recently published in Journal of Experimental Medicine (1). This study, by Fabrina M. Gaspal and et al, made an interesting observation that mice triple deficient in OX40/CD30/Foxp3 are healthy. It appears that OX40/CD30 pathways control autoimmune potential of self-specific T cells. The simple explanation I favor is that in the absence of OX40/CD30 signaling, effector/memory T cell differentiation is impaired in general and as a consequence, self-specific T cells loose the capability to damage the tissue. Of course, the one caveat of the paper is that we have no idea whether those triple deficient mice are capable of mounting a proper immune response to non-self antigenic challenge or infection. If they cannot, then the absence of autoimmunity is the direct consequence of immunodeficiency (similar to gamma-c receptor deficient mouse model). However, if they could respond to non-self antigenic challenge or infection, then this model has made an unique contribution to our understanding of Foxp3 biology.

David Usharauli

(1) http://jem.rupress.org/content/208/8/1579.abstract