Abstract IA09: The commensal microbiota as instructors and arbiters of homeostatic and pathogenic immune responses

The vertebrate intestinal tract is colonized by hundreds of species of bacteria that outnumber the total cells in the host, yet must be compartmentalized and tolerated to prevent invasive growth and harmful inflammatory responses. A key function of commensal microbes is to contribute to the adaptive immune repertoire and to diverse lymphocyte effector functions. T cell responses against non-invasive commensals, as exemplified by responses elicited by the segmented filamentous bacteria (SFB) and Helicobacter hepaticus, contribute to shaping the repertoire of effector/memory and regulatory T cells. SFB adhere to the epithelium in the terminal ileum of mice and induce differentiation of Th17 cells that normally protect the mucosal barrier, but contribute to autoimmune disease in susceptible mice. H. hepaticus colonizes the large intestine and induces Treg cells in wild type mice and inflammatory Th17 cells in IL-10-deficient mice. How T cells elicited by commensal bacteria can influence autoimmunity is a central question that remains unsolved. We are studying the antigenic specificity of microbiota-induced T cells and the mechanisms by which their functions are acquired upon interaction with distinct commensal species. We find that induction of SFB-specific Th17 cells and H. hepaticus-specific Treg cells requires priming and polarization of antigen-specific RORgt-expressing CD4+ T cells (also expressing Foxp3 for Tregs) in the draining lymph nodes. Induction of IL-17 in lamina propria Th17 cells occurs only in regions with adjacent SFB colonization. Acquisition of Th17 effector functions requires the local activation of IL-22-producing innate lymphoid cells (ILC3). These, in turn, act on intestinal epithelial cells to induce secretion of serum amyloid A proteins, SAA1 and SAA2, that activate primed RORgt+ T cells. Expression of the Th17 cell effector program requires formation of a complex of RORgt with a DEAD-box RNA helicase and a long noncoding RNA that, together, confer transcriptional activity at target loci. Requirements for induction of Treg versus Th17 cells will be discussed, as will be the potential role of SAAs in inflammation. These studies in mice are not only relevant for human autoimmune diseases, many of which have Th17 cell involvement, but may also provide insights into how commensal microbe-specific T cell responses could be harnessed for mucosal vaccination and cancer immunotherapy. Indeed, it has recently become evident that the microbiota plays an important role in patient responses to cancer chemotherapy and checkpoint immunotherapy. A better understanding of how individual or communities of bacteria (or commensal viruses and fungi) regulate tumor-specific T cell responses may pave the way for microbiota-based cancer therapies. Citation Format: Teruyuki Sano, Mo Xu, Lin Wu, June-Tong Lee, Wendy Huang, Yi Yang, Gretchen Diehl, Dan R. Littman. The commensal microbiota as instructors and arbiters of homeostatic and pathogenic immune responses [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr IA09.