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.
Bacterial infections of the gastrointestinal tract are a leading cause of diarrhea worldwide, with Salmonella spp. and enteropathogenic and enterohemorrhagic E. coli (EPEC, EHEC) being among the most common causative bacterial agents. Greater understanding of the immune parameters associated with protection from intestinal infection is required to provide a solid foundation for the development of novel and improved protective or therapeutic strategies against these infections. Here, we propose to define the contribution of MR1-restricted Mucosal-Associated Invariant T (MAIT) cells, a T cell population that is very abundant in the human gastrointestinal tract, to protective immunity during intestinal infection. We have developed a novel tractable small animal model that overcomes previous difficulties to study MAIT cells in vivo, and propose to use this model to study the role of MAIT cells during infection with Salmonella typhimurium or Citrobacter rodentium, a mouse model for human EPEC and EHEC infection. These studies will improve our understanding of intestinal mucosal immunity and may result in novel and improved protective strategies.
