MR1 and MAIT Cell Function in Intestinal Infection

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Abstract Mucosal-associated invariant T (MAIT) cells are an evolutionarily conserved subset of innate-like T cells that localize preferentially to the gastrointestinal (GI) tract and recognize microbial vitamin metabolite antigens. However, the molecular and cellular mechanisms of protective MAIT cell functions and their regulation in intestinal immunity are not known. Our long-term goal is to understand the role and function of MAIT cells in intestinal immunity. Based on our Preliminary Studies, we hypothesize that MAIT cells play a protective role during intestinal infection with Salmonella typhimurium or Citrobacter rodentium. Using a newly established, traceable MAIT TCR retrogenic mouse model, we will test our central hypothesis in the following three specific aims: in Aim 1, we will define the antigen-presenting cells systemically and in the intestinal tract that are critical for MAIT cell activation during infection. In Aim 2, we will determine the role of MAIT cells in early, innate and late, adaptive immunity during intestinal infection with S. typhimurium or C. rodentium. In Aim 3, we will utilize targeted, antigen-mediated activation of MAIT cells to determine the therapeutic potential of MR1/MAIT cells to enhance protective intestinal immunity. Together, these studies will define the role of MAIT cells in intestinal infection and will lay the foundation to target these cells to enhance protective intestinal immune responses. Together, these studies are expected to significantly advance our understanding of MR1/MAIT cell biology.