Book excerpt: Mucosal-associated invariant T (MAIT) cells are a class of unconventional T cells that are defined by a limited T cell receptor (TCR) repertoire that recognize microbial riboflavin-derivative antigens presented by the major histocompatibility complex (MHC) class I-like protein, MR1. Importantly, commensal species of bacteria and yeast in a healthy microbiome generate these metabolite MAIT antigens. Thus, MAIT cells are likely mediators of commensal-specific interactions due to their broad antigen recognition, tissue location and abundance. However, since in vivo characterization of MAIT cells has been minimal, their role in human mucosal tissues is still poorly understood. For example, it is not clear whether functional MR1 is expressed in healthy mucosal tissues and if so, by what classes of immune cells. In this thesis, I use flow cytometric analysis to characterize MAIT cells and assess functional MR1 expression within colonic biopsies and peripheral blood samples from healthy donors. I show extensive MR1 expression among multiple colonic-resident immune cells including antigen-presenting cells and T cells. MAIT cells presented an activated phenotype within the colon with heightened expression of activation markers among the tissue-resident immune cell population. These data suggest that MAIT cells may be continually responding to the microbiota in barrier sites. In addition to their role in normal tissue homeostasis, MAIT cells acquire potent effector function in response to proinflammatory signals, which synergize with a TCR signal. This raises the question how MAIT cells are regulated within inflamed tissues where they presumably would be receiving both of these signals. To address this, I examined the transcriptome of MAIT cells from blood and oral mucosal tissues and found that tissue MAIT cells express an immunoregulatory gene signature, which includes expression of the inhibitory receptor CTLA-4. Further, I define the requirements for surface CTLA-4 protein expression on MAIT cells and demonstrate that inflammatory cytokines are sufficient to elicit and maintain CTLA-4 protein expression on the MAIT cell surface in the absence of a TCR signal. Therefore, control of CTLA-4 expression is fundamentally different from conventional T cells, which require a TCR signal. This mechanism may serve to limit cell-mediated tissue damage in response to commensal antigen within inflamed tissues. Together, this work contributes valuable ex vivo and mechanistic insight into human MAIT cell immunoregulation within healthy and inflamed mucosal tissues.