Wednesday, April 24, 2024
4/24/2024
PROJECT SUMMARY. A dysregulated intestinal immune response is a hallmark of inflammatory bowel disease (IBD), but current therapies that target these responses often exhibit poor long-term efficacy. The reasons for this poor efficacy likely stem from an incomplete understanding of the immunological and microbial interactions that lead to disease. Recent studies examining immune interactions in human IBD patients have highlighted dysregulated interactions between immunoregulatory and inflammatory T cells as a key feature of disease. However, the exact cellular players involved and how these dysregulated interactions occur remain unclear. In efforts to close these gaps in knowledge, our long-term goals are to define the mechanisms that govern the interactions between immunoregulatory and inflammatory T cells and how these interactions can be targeted to improve IBD therapeutics. In our preliminary data, we show that mice carrying conventional T cell (i.e. aß T cell receptor+)-specific deletions of STAT3 and BATF develop an aggressive spontaneous colitis that closely resembles intestinal inflammation that is characteristic of human IBD. Intriguingly, the known mediators and suppressors of disease (IL-17-producing Th17 and Foxp3+ T regulatory (Treg) cells), are equivalent in STAT3/BATF-double deficient mice and disease-free STAT3 and BATF-single deficient mice. These data suggest that a STAT3/BATF- regulated transcriptional program induces Th17/Treg-independent immunoregulatory function that is critical for maintaining intestinal homeostasis. Intestinal disease in conventional T cell STAT3/BATF-deficient mice was marked by the rapid accumulation of microbiota-dependent inflammatory ¿d T cells, resembling those found in lesional colonic tissues of IBD patients. These data suggest that STAT3/BATF-expressing conventional T cells interact with the microbiota and ¿d T cells to suppress disease. The objective of this study is to determine how STAT3 and BATF regulate the interactions and functions of conventional immunoregulatory T cells and to define how microbiota-dependent ¿d T cells contribute to disease. Here we hypothesize that conventional T cell STAT3 and BATF cooperatively regulate a gene network that influences interactions with the microbiota and pathogenic ¿d T cell responses in IBD. We will test this hypothesis via two aims in which we will 1) define the STAT3/BATF-regulated transcriptional network that governs conventional-¿d T cell interactions in IBD and 2) determine the role the microbiota-induced ¿d T cells in driving IBD. The results of this work will be highly significant and innovative as we have identified a novel mechanism by which conventional T cells maintain intestinal homeostasis and developed a new murine model to examine interactions of these cells with the microbiota and ¿d T cells in disease. Further, our studies will provide insight into new therapies that may act to bolster STAT3/BATF+ conventional T cells to prevent the onset of IBD.
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