Recipient mucosal-associated invariant T cells control GVHD 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 class 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 likely 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 that appear to represent pathways controlled by similar, IL-17A-dependent mechanisms. Thus, MAIT cells act to control 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.

TCR and Inflammatory Signals Tune Human MAIT Cells to Exert Specific Tissue Repair and Effector Functions

“…This is most clearly seen in the study of non-obese diabetic (NOD) mice, in which the genetic absence of MR1 leads to loss of mucosal integrity and bacterial translocation in the steady state (Rouxel et al, 2017). A similar epithelial protective role is seen in a model of graft versus host disease (Varelias et al, 2018). This adds to existing data indicating a classical immune protective role against infection, for example, in the lung, following bacterial challenge .…”

An overview on the identification of MAIT cell antigens

“…The discovery of 5-OP-RU and 5-OE-RU as very potent Ags and the development of MR1-tetramers, 5,42 now available from the National Institutes of Health, USA, have opened up the field to start elucidating the roles of MAIT cells in anti-microbial immunity, 19,[66][67][68][69][70] in sensing of metabolic changes such as in cancer, stress and cell damage, 65,71 as well as in immunopathology. [72][73][74] The tetramers have also allowed further characterization of the phenotypic identity of MAIT cells and their development, with individual-and age-specific differences now being investigated.…”

Computer Modelling and Synthesis of Deoxy and Monohydroxy Analogues of a Ribitylaminouracil Bacterial Metabolite that Potently Activates Human T Cells

“…Despite its instability in aqueous solutions, 5‐OP‐RU has quickly become an important tool in immunology owing to its remarkably potent in vitro activation of MAIT cells (EC 50 =2 p m ) and consequent immunostimulatory properties. Since its discovery and synthesis, 5‐OP‐RU has been used to investigate the role of MAIT cell activation in animal models of gastritis, graft‐vs.‐host disease and HIV infection . It has also been used to form sophisticated immunological reagents that are currently accepted as the gold standard probes for MAIT cell identification .…”