Control of intestinal inflammation through CD101 expression

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Dysregulated host-microbe interactions in genetically susceptible individuals have been implicated in the pathogenesis of inflammatory bowel diseases (IBDs). However, molecules and signalling pathways controlling the interactions of the intestinal microflora with the immune system of the patient and their role in the suppression of intestinal inflammation have been rarely identified. We have recently characterized CD101, a negative costimulatory molecule shared by myeloid and lymphoid cell subsets, as critical factor for the control of T cell proliferation and Th17 differentiation in a chronic T cell transfer colitis model. Recipients of T cells from wild-type mice exhibited less severe intestinal pathology than CD101-/- littermates correlating with an acquisition of CD101-expression on T cells and decreased bacterial translocation. Conversely, human IBD patients exhibited lower numbers of CD101-expressing T cells correlating with increased systemic immune responses to enteric bacterial antigens. Based on these findings we propose that CD101 is a novel clinical marker for tissue-specific inflammation in IBD. Thus, the overall goal of the present proposal is to determine the role of CD101 in directing tissue-specific immune protection. Although the mechanisms by which CD101 interferes with T cell activation are unknown, our preliminary data support the hypotheses that a lack of CD101 expression on T cells inhibits the generation of regulatory T cells, triggers T cell proliferation and Th17 responses and subsequently promotes intestinal inflammation and bacterial translocation. Thus, we aim to: 1) explore the regulation of CD101-expression under physiologic and inflammatory conditions in response to intestinal commensal bacteria; 2) determine the impact of CD101-expression on the protection from colitis; define the role of CD101 on 3) IL-2R- and FoxP3-expression and 4) the generation of regulatory T cell and Th17 responses; 5) specify the interaction(s) of T cells with myeloid cells in the presence and absence of CD101; and 6) correlate the expression of CD101 on T cells in IBD patients to the clinical disease score, the reactivity of serum samples to oligosaccharides of intestinal bacteria and shifts in the balance of Treg-Th17 homeostasis.