Role of MR1-Restricted MAIT Cells in Intestinal Infection

Brigham And Women'S Hospital, Boston MA

Investigators

Abstract

? DESCRIPTION (provided by applicant): 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. MAIT cells are very abundant in human blood, liver and GI tract, but are very rare in common laboratory mouse strains. Barriers to understand critical features of MAIT cell functions are the lack of suitable small animal models and of markers to trace MAIT cells in vivo. Our long-term goal is to understand the role and function of MAIT cells in intestinal immunity. Based on our identification of a MAIT cell hybridoma that recognizes Salmonella typhimurium, the objective here is to establish a new retrogenic (Rg) mouse model to investigate the function of MAIT cells during intestinal infection. Our central hypothesis is tht MAIT cells have a protective function during S. typhimurium infection by producing IFN-?, IL-17, TNF-?, and IL-22, and that the rapid activation of functionally distinct MAIT cell subsets is regulated by a combination of TCR- and cytokine-mediated signals. We will test our central hypothesis in the following two specific aims: in Aim 1, we will define the mechanisms that determine and regulate MAIT cell functions during Salmonella infection. In Aim 2, we will determine what influence MAIT cells have on the course of Salmonella infection, including the role of IFN-?, IL-17, TNF-?, and IL-22 in protection mediated by MAIT cells. Together, these studies will define the role of MAIT cell, the effector functions that are critical for protection,and the mechanisms that determine and regulate MAIT cell functions during intestinal infection. This work has significant impact, because understanding the functions of MAIT cells in intestinal immunity is critical to successfully target these cells in novel protective strategies for intestinl infections. Furthermore, the novel traceable Rg MAIT cell mouse model is expected to have additional utility for elucidating the factors that control MAIT cell development and their functio in homeostasis and intestinal inflammation, including inflammatory bowel diseases. Therefore, these studies are expected to significantly advance our understanding of MR1/MAIT cell biology.