IL-17 response to airborne fungi are driven by gut commensal pathobiont C. albicans

A new paper in @CellCellPress from Bacher/Scheffold lab showed that IL-17+ T cell response to airborne #fungus such as #Aspergillus fumigatus found in individuals with #asthma,#COPD, and CF,are in fact expanded by gut commensal pathobiont #Candida #albicans via #crossreactivity.

— David Usharauli (@3DiMMUNE) February 23, 2019

1. majority of IL-17+ #Tcells found in healthy donors are specific C. albicans. #Immunology #TH17 #fungi pic.twitter.com/3WITidrcCn

— David Usharauli (@3DiMMUNE) February 23, 2019

3. In fact, when C. albicans-specific T cells were depleted from #Aspergillus 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 #crossreactive to C. albicans. pic.twitter.com/cZEu50Uwep

— David Usharauli (@3DiMMUNE) February 23, 2019

5. similar expansion of Aspergillus fumigatus-specific T cells producing IL-17 were observed in individuals with #crohnsdisease too. pic.twitter.com/L0VbmCcFj5

— David Usharauli (@3DiMMUNE) February 23, 2019

As both #fungi are naturally available in the environment any #immunopathology 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???

— David Usharauli (@3DiMMUNE) February 23, 2019

No going back: conventional B cells (B2) could trans-differentiate into innate-like B cells (B1) but not vice versa

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.

— David Usharauli (@3DiMMUNE) February 16, 2019

1. This is a model system the authors set up to do it. Normally, #transgenic B cells express either VH12 (B1) or B1-8 (B2) only. However, after cre #recombination, VH12 is #replaced with B1-8 and vice versa. So, B1 should start expressing B2 receptor and B2 --> B1 receptor. pic.twitter.com/L4J1nBJENh

— David Usharauli (@3DiMMUNE) February 16, 2019

3. The same outcome was observed in an in #vivo setting too. Conventional B2 cells could produce #functioning B1 cells after #BCR swap but not vice versa. pic.twitter.com/cXHJLWaHsv

— David Usharauli (@3DiMMUNE) February 16, 2019

#Summary: conventional B cells (a.k.a B2 cells) still harbor #potential for trans-differentiate into B1 cells while B1 cells lack such quality.

Why is that? B1 produce so called natural "housekeeping" antibodies specific for some self antigens exposed during cell #senescence.

— David Usharauli (@3DiMMUNE) February 16, 2019

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 😎

— David Usharauli (@3DiMMUNE) February 16, 2019

An antigen from gut commensal Bacteroides thetaiotaomicron (B. theta) is recognized by Foxp3+ Tregs

1. B.theta-specific T cells when transferred into #antibiotic-treated and B.theta #colonized T cell-deficient mice (#RAG1-KO) develop into #Foxp3+ #Tregs 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. pic.twitter.com/TD0pnnxgAR

— David Usharauli (@3DiMMUNE) February 9, 2019

3. The authors were able to identify a #specific #epitope in B.theta recognized by B.theta-specific T cells. The #sequence, EEFNLPTTNGGHAT, were mapped in BT4295 predicted to be a SusE/SusF #lipoprotein in outer #membrane (OM). pic.twitter.com/rH5cQHQcVN

— David Usharauli (@3DiMMUNE) February 9, 2019

In #summary, this study showed that certain gut #commensal #microbiota species, in this case, #Bacteroides thetaiotaomicron (B. theta) are recognized by #Tregs and even induce #effector T cell differentiation though the host stays healthy because Tregs regulate effector T cells.

— David Usharauli (@3DiMMUNE) February 9, 2019

Another point is whether #microbiota-specific Tregs are #denovo induced or #amplified from existing ones. I personally think it is a latter. Most #Tregs develop from #CD25-negative #precursors poised for Foxp3 expression & such precursors are all #thymus derived, in my opinion.

— David Usharauli (@3DiMMUNE) February 9, 2019