Book excerpt: MHC-related protein 1 (MR1) is the non-classical MHC class I molecule that is responsible for the selection and development of mucosal-associated invariant T (MAIT) cells. The Mr1 gene is monomorphic and highly conserved among mammals, while MAIT cells display an invariant V[alpha] paired with limited V[beta] TCR chains. Despite the ubiquitous detection of MR1 transcripts and intracellular protein, it has been difficult to detect expression of endogenous MR1 on the plasma membrane resulting in the long-pending question of the physiological role of endogenous MR1. Additionally, although previous studies have implicated antigen presentation by MR1to MAIT cells in antibacterial immunity, the mechanism remains undefined. To unveil the physiological role of MR1 and MAIT cells in the immune system, two main approaches were taken in this dissertation: generating new monoclonal antibodies (mAbs) against mouse MR1 to facilitate the detection of endogenous MR1, and establishing in vivo and in vitro models to study MAIT cell responses to microbes. Employing the new mAbs, endogenous MR1 was found to be transiently expressed on the cell surface. More specifically, under basal conditions, low levels of endogenous MR1 could be stabilized at the cell surface by a unique mAb in a functional conformation that activates MAIT cells. In addition, the new mAbs also helped to identify double positive thymocytes, macrophages, and DCs as potential APCs for MAIT cell development and activation. To further probe the function of MR1 and MAIT cells, MAIT cell-deficient mice (as a result of MR1 deficiency) were subjected to bacterial or viral infection as well as a chemical-induced colonic injury. While MR1-restricted MAIT cells were found not to be required for the clearance of the infections of uropathogenic Escherichia coli and West Nile virus, they played a non-redundant role in protective immunity against the infection of Mycobacterium bovis BCG. Taking advantage of an in vitro co-culture assay, MAIT cells were found to inhibit the intracellular mycobacterial growth in macrophages. The antibacterial activity was dependent on the MR1 selection during development, an IL-12/23p40 signal, and IFN-[gamma] secretion. MR1 deficiency also resulted in the lack of proper epithelial regeneration in response to colonic injury. Collectively, research in this dissertation has provided evidence that MR1-restricted MAIT cells play a unique role in the immune system, during both homeostasis and infection.