Thursday, August 3, 2017

Th2A subset drives allergic phenotype in humans

TH2 cells were initially identified based on their capacity to make IL-4 and drive B cell antibody class switch recombination to IgG1  and IgE. However, more recently it became clear that TH2 cells consist of several subtypes each with its own unique specialization in particular effector function such as IL-13 or IL-25 production that have nothing to do with antibody production. 

Similarly, canonical TH2 cells were thought to be responsible for allergy phenotype in humans (and mice as well). However, new study in Science Translational Medicine suggests new subset of TH2 cells, called TH2A subset, is mainly responsible for food allergy phenotype

The authors carried out magnetic enrichment of T cells harvested from allergic patients using HLA-II tetramers. Compared to non-allergic individuals, allergic patents showed expansion of a special population of TH2 cells expressing CD161 and CD49d




Interestingly, patients undergoing antigen-specific desensitization showed selective loss of these TH2A cells.



In summary, it is clear that different subset of TH2 cells exist, some naturally others only during pathology, to deal with various foreign antigenic entities.

posted by David Usharauli

      

Wednesday, July 26, 2017

IBD converts tolerant antigens into immunogenic

Inflammatory bowel disease (IBD) is a pathological condition wherein body's immune cells wrongly attack its own or commensal microbiota-derived antigens that initiates a vicious cycles of permanent inflammation.
 
However, it is still not clear whether immune system attacks "new" antigens from microbiota or simply it loses adaptive tolerance to "old" ones. 
 
New study in Science Immunology tried to answer it to the extent it was possible to do in mouse model.
 
First, the authors generated IBD condition in mice by treating them with DSS + anti-IL10R. Keep in mind this is highly artificial model. Then, they transferred naïve T cells from previously established transgenic T cell lines specific for unknown commensal antigens that were known to drive Treg phenotype. Naïve T cells transferred into control WT mice generated Tregs while the naïve T cells transferred into IBD-conditioned mice preferably developed into effector T cells.
 
 
 
When analyzed for antigen specificity, the authors found that transgenic naïve T cells were reactive to antigens derived from Helicobacter species that have expanded during IBD-conditioning.
 
 
 
In vivo studies also confirmed that Helicobacter species could induce Treg generation from naïve transgenic T cells in "normal" condition.
 
 
 
Interestingly, transfer of T cells specific for other microbiota species that also underwent expansion during IBD-conditioning did not produce T cell expansion.
 
 
 
Finally, transfer of Treg-TCR transgenic naïve T cells into RAG-KO mice produced IBD when co-injected with Helicobacter species.
 
 
 
What these data indicate? In my view the authors made one correct and one wrong interpretation. First, they were correct to conclude that T cell response to IBD could be directed to "old" microbiota antigens rather than "new" never before seen microbiota-derived antigens. So basically in IBD we are losing tolerance rather than gaining immunity to microbiota antigens.
 
However, they made wrong conclusion that naïve T cells are converted into Tregs in vivo based on context (normal versus IBD). In their study loss of Treg generation is inhibited either during IBD-conditioning or in RAG KO hosts which could argue alternatively that such outcome has to do with failure of naïve T cells to interact with existing Tregs specific for the same or similar antigens in these scenarios (IBD or RAG-KO).
 
posted by David Usharauli
 
 
        

Sunday, July 16, 2017

Identification of prostate-antigen specific natural Tregs (in mice)

Foxp3+ Tregs are central player in maintaining tolerance to self and other environmental antigens. However, till to this date we know little of their antigen specificity. It is because unlike conventional CD4+ T cells, Tregs do not secrete [upon antigen recognition] any cytokine that uniquely identifies them. The best marker is still Foxp3 molecule, an intracellular transcription factor.   

So it is always interesting to see new study that could identify Treg epitope, such as this new paper in Immunity that provided evidence that in mice peptide spanning residues 646–658 of prostate-specific TRPM8 channel-associated factor 3 protein (Tcaf3) is a natural epitope for thymic MJ23 TCR transgenic Treg development.

The authors showed that development of MJ23+ Tregs from adoptively transferred MJ23+ thymocytes (un-differentiated T cells) were only supported in hosts expressing intact Tcaf3 (and not in Tcaf3 KO mice).   



Next, using sensitive tetramer based antigen-specific T cell detection, the authors showed that WT mice also harbored Tcaf3[646–658]-tetramer specific T cells that were enriched in Tregs compared to other antigen-specific T cells (2W1S). Interestingly, Aire-KO mice which do not efficiently express peripheral antigens in the thymus harbored reduced numbers of Tcaf3[646–658]-tetramer specific Tregs.



Finally, the authors showed that prostate tissue from Aire KO mice harbored significantly more Tcaf3[646–658]-tetramer specific Tregs compared to prostate tissue from normal mice. I found these particular results problematic because should not normal mice prostate supposed to contain Tregs to prevent autoimmunity? Or are Tregs keeping autoreactive T cells in check in draining lymph nodes? 




In summary, this study showed that in mice prostate-specific Tcaf3[646–658] epitope is a natural ligand that selects Tregs in a Aire-dependent manner.

posted by David Usharauli