Title: Human mucosal-associated invariant T (MAIT) cells in inflamed tissues

Abstract

Abstract Mucosal-associated invariant T (MAIT) cells recognize bacterial metabolites via a semi-invariant T cell receptor (TCR) presented by MHC-like molecule MR1. Once activated, MAIT cells are a potent effector population with cytotoxic and pro-inflammatory properties. We recently reported that a TCR signal is not sufficient to elicit effector function, instead pro-inflammatory cytokines in addition to a TCR signal are required for sustained MAIT cell effector functions. We proposed that this requirement allows MAIT cells to distinguish between commensal (TCR signal only) and pathogenic bacteria (TCR signal + inflammation). We next wanted to address how MAIT cells function within an inflamed tissue environment. Specifically, if inflammation resulted in increased MAIT effector function or an exhausted phenotype because of the sustained stimuli. We obtained gingival tissue and matched blood from donors undergoing periodontic surgery for various inflammation-related diseases. MAIT cells within inflamed mucosa showed increased effector function directly ex vivo compared to blood including expression of granzyme B and TNFa. RNAseq analysis of MAIT cells from inflamed mucosal tissue revealed a distinct transcriptional signature compared to MAIT cells in the blood. We observed a significant upregulation of chemotaxis and activation genes as well as inhibitory genes from multiple immune-modulatory pathways. Our data suggest that MAIT cells in inflamed tissues can maintain effector function, but also express immunomodulatory genes that presumably serve to avoid unwanted tissue damage.