Recipient mucosal-associated invariant T cells control GVHD within the colon
Antiopi Varelias, … , Philip Hugenholtz, Geoffrey R. Hill
Antiopi Varelias, … , Philip Hugenholtz, Geoffrey R. Hill
Published April 9, 2018
Citation Information: J Clin Invest. 2018;128(5):1919-1936. https://doi.org/10.1172/JCI91646.
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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.

Authors

Antiopi Varelias, Mark D. Bunting, Kate L. Ormerod, Motoko Koyama, Stuart D. Olver, Jasmin Straube, Rachel D. Kuns, Renee J. Robb, Andrea S. Henden, Leanne Cooper, Nancy Lachner, Kate H. Gartlan, Olivier Lantz, Lars Kjer-Nielsen, Jeffrey Y.W. Mak, David P. Fairlie, Andrew D. Clouston, James McCluskey, Jamie Rossjohn, Steven W. Lane, Philip Hugenholtz, Geoffrey R. Hill

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Figure 5

Recipient MAIT cells attenuate proinflammatory donor CD4+ T cell expansion in the colon.

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Recipient MAIT cells attenuate proinflammatory donor CD4+ T cell expansi...
(A) B6.WT and B6.MR1–/– mice were lethally irradiated, transplanted with BALB/c.WT BM (10 × 106) and BALB/c.luciferase+ T cells (3 × 106) and organs imaged at days 7 and 14 after transplant. Representative BLI images of the spleen, liver, lung, and GI tract (including mLNs) are shown. (B) Quantitated BLI at days 7 (top) and 14 (bottom) is shown. Data are pooled from 2 independent experiments for each time point. Day 7, n = 5–7 per group; day 14, n = 11 per group. (C) Frequency of proliferating donor CD4+ T cells in the colon lamina propria at day 14, as determined by intracellular Ki-67 expression. (D) Frequency of apoptotic donor CD4+ T cells in the colon lamina propria at day 14, as determined by intracellular active caspase-3 expression. Data combined from 2 replicate experiments are shown. n = 5 – 9 per group. Data analyzed using the Mann-Whitney U test.