Recipient mucosal-associated invariant T cells control graft-versus-host-disease within the colon

Abstract Mucosal-associated invariant T (MAIT) cells are a unique innate-like T-cell subset that responds to a wide array of bacteria and yeast through recognition of riboflavin metabolites presented by the MHC I-like molecule, MR1. Here we demonstrate using MR1 tetramers that recipient MAIT cells are present in small but definable numbers in graft-versus-host disease (GVHD) target organs and protect from acute GVHD in the colon following bone marrow transplantation (BMT). Consistent with their preferential juxtaposition to microbial signals in the colon, recipient MAIT cells generate large amounts of IL-17A, promote gastrointestinal tract integrity, and limit the donor alloantigen presentation that in turn drives donor Th1 and Th17 expansion specifically in the colon after BMT. Allogeneic BMT recipients deficient in IL-17A also develop accelerated GVHD, suggesting MAIT cells regulate GVHD, at least in part, by the generation of this cytokine. Indeed, analysis of stool microbiota and colon tissue from IL-17A−/− and MR1−/− mice identified analogous shifts in microbiome operational taxonomic units (OTU) and mediators of barrier integrity which represent pathways controlled by similar, IL-17A-dependent mechanisms. Thus, MAIT cells act to control intestinal microbiota and barrier function to attenuate pathogenic T-cell responses in the colon, and given their very high frequency in humans, likely represent an important population in clinical BMT.