Harnessing single cell analysis to characterize the role of MAIT cells in ulcerative colitis

Abstract

Abstract Ulcerative colitis (UC) is an increasingly prevalent form of inflammatory bowel disease, characterized by chronic T cell mediated inflammation of colonic mucosa. UC is likely caused by a confluence of immune dysregulation, genetics, gut microbiome dysbiosis, and environmental factors. Mucosal associated invariant T (MAIT) cells are a sub-population of CD8+ T cells that recognize microbial derived vitamin B2 based antigens and are a significant population in homeostatic mucosa. MAITs are likely a heterogenous population and a subset of MAITs may “link” microbiome dysbiosis, environmental factors and chronic colonic inflammation. To assess the role of MAIT cells in UC, we have analyzed MAITs isolated from matched colonic biopsies, both uninflamed and inflamed mucosa, and blood from a cohort of UC patients. Utilizing MR1 tetramers and single cell analysis techniques, we confirmed a decrease in MAIT cell frequency in peripheral blood of UC patients relative to healthy donors. We have also found an increase in MAIT frequency in inflamed colonic mucosa of UC patients relative to uninflamed mucosa. Single cell gene expression profiling revealed tissue specific differences between blood MAIT cells and colonic MAIT cells as well as a trend for higher expression of activation and pro-inflammatory genes in MAITs isolated from inflamed mucosa. Most intriguingly, single cell TCR sequencing revealed the expansion of a subset of MAITs in inflamed colonic mucosa with a distinct TCRVb and CDR3b sequence. This suggests that a sub-population of MAIT cells in inflamed colonic mucosa are reacting to unique microbial ligands. A new cohort will extend these findings, but our preliminary results support a role for MAIT cells in the pathology of UC.