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

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