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.
Salmonella infections can cause a range of intestinal and systemic diseases in humans and animals and are an important public health priority worldwide. Greater understanding of the immune parameters associated with protection from Salmonella infection is required to provide a solid foundation for the development of novel and improved protective strategies against these infections. Here, we propose to define the contribution of MR1-restricted Mucosal-Associated Invariant T (MAIT) cells to protective immunity during Salmonella infection by developing a novel tractable small animal model that overcomes previous difficulties to study MAIT cells in vivo. These studies will improve our understanding of intestinal mucosal immunity and may result in novel and improved vaccine strategies.
