PROJECT SUMMARY The commensal microbiota inhabiting the gastrointestinal tract and other mammalian mucosal surfaces. plays fundamental roles on the induction, training and function of the host immune system, but the exact mechanisms that regulate these interactions are not fully understood. Understanding these mechanisms is a crucial step towards designing new therapeutic approaches to correct immune dysfunction caused by dysbiosis and potentially other conditions. Our initial studies show that alterations of the intestinal microbiota induced by oral administration of antibiotics selectively disrupt long-term maintenance of antigen-specific memory CD4+T cells primed in untreated mice, and impairs secondary responses to infection. In addition, we found that treatment of mice with antibiotics is associated with reduced expression of the cytokine IL- 15, which is required for maintenance of memory T cells. Together, these results led us to hypothesize that the commensall microbiota regulates memory T cell responses by stimulating the expression of factors that promotes differentiation and/ or maintenance of antigen-specific memory T cells. In this application, we will test this hypothesis. The specific aims proposed are 1) Identify mechanisms underlying the requirement of the intestinal microbiota for T cell memory and 2) Determine if antibiotic treatment alters memory T cell responses in human subjects. We anticipate that these studies will shed light on the mechanisms underlying the crosstalk between the commensal microbiota and the immune system and may inform the design of new and improved vaccine strategies