A NOVEL MOUSE MODEL OF CROHN’S DISEASE DRIVEN BY THE INTERACTION OF CD4 T CELLS AND GUT MICROBIOTA-RESPONSIVE γδ T CELLS

Abstract

Abstract Inflammatory bowel disease (IBD) is a spectrum of disorders, namely Crohn’s Disease (CD) and Ulcerative Colitis (UC), characterized by distinct patterns of intestinal inflammation, a dysregulated intestinal immune response, and an altered gut microbiota. Given the growing number of new IBD diagnoses (70,000 new cases reported each year) and the inconsistent results of current treatment options, there is a major unmet need to understand IBD pathophysiology to develop more effective treatments. Previous reports indicate that IBD patients have an altered gut microbiota that can influence the development of inflammatory innate and adaptive immune cells that cause intestinal tissue damage and drive IBD pathogenesis. In particular, innate-like γδ T cells have been shown to accumulate within lesional tissue of CD patients and exhibit an inflammatory profile. However, the role of γδ T cells in promoting CD is not well understood, partially due to a lack of mouse models that accurately mimic human γδ T cell phenotypes. Thus, there is a critical need to more deeply understand conventional-γδ cross-talk in the intestine and develop novel animal models that accurately recapitulate these interactions during disease. We have previously shown that the transcription factors (TFs) STAT3 and BATF play critical roles in pathogenic CD4 T cell differentiation, but their roles in modulating interactions between adaptive and innate-like T cells are less clear. In our preliminary work, we surprisingly found that mice with conventional T cell-specific deletions in STAT3 and BATF, but not each individual TF, developed an aggressive spontaneous colitis with pathology that mimics the intestinal damage seen in Crohn’s disease patients. This spontaneous colitis was hallmarked by elevated numbers of inflammatory (i.e., high IFN-γ producing) γδ T cells in the intestines, which mimic those found in a subset of IBD patients. Importantly, depletion of γδ T cells in this model resulted in diminished disease, implicating these cells as key mediators of CD-like intestinal inflammation. γδ T cells in our model were largely localized between colonic crypts and in close proximity to the gut microbiota, suggesting that they may be influenced by changes in gut microbes. Indeed, we observed that STAT3/BATF-deficient mice exhibited an altered gut microbiota which was required for the dysregulated γδ T cell response. Taken together, our data indicate that STAT3/BATF-expressing conventional CD4 T cells regulate gut microbes that would otherwise drive the generation of inflammatory γδ T cells that contribute to CD-like disease. Therefore, a better understanding of microbe-γδ T cell interactions is imperative for understanding intestinal homeostasis and for defining therapies that may prevent the onset of IBD. Figure 1 Graphical abstract. This project seeks to identify the interactions between T cells and gut microbiota in driving IBD, more specifically Crohn’s disease.