Project Summary It is now widely appreciated that gut commensal bacteria play a major role in health and disease. While dysregulation of the intestinal flora has been shown to contribute to many autoimmune abnormalities, specific relationships between particular microbial species and the state of host immunity have been unraveled for only a small number of organisms. Recent studies have supported the notion that segmented filamentous bacterium is a key gut commensal bacterium for driving mucosal Th17 responses, which is arguably one of the most exciting discoveries in the field. However, there exist intense debates on key aspects of the development of mucosal Th17 cells. Taking advantage of unique tools recently developed, we aim to address three important questions: (1) Which cytokines are required for SFB-specific Th17 cell induction; (2) What are the specific mucosal APC subsets that present bacterial antigens; and (3) How does antigen affinity of TCRs impact on Th17 differentiation. The feasibility of this proposal is supported by (1) many unique tools that we developed, including CD4 T cell hybridomas, novel TCR transgenic mice and transgenic Listeria monocytogenes; and (2) our first-hand experience in mucosal immunology in general and with this experimental system in particular. Insights to be derived from this project will be important for understanding and harnessing mucosal immune responses.