Recipient mucosal-associated invariant T cells control GVHD within the colon

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 & 2 others Philip Hugenholtz, Geoffrey R. Hill

Research output: Contribution to journalArticleResearchpeer-review

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.

Original languageEnglish
Pages (from-to)1919-1936
Number of pages18
JournalJournal of Clinical Investigation
Volume128
Issue number5
DOIs
Publication statusPublished - 1 May 2018

Cite this

Varelias, A., Bunting, M. D., Ormerod, K. L., Koyama, M., Olver, S. D., Straube, J., ... Hill, G. R. (2018). Recipient mucosal-associated invariant T cells control GVHD within the colon. Journal of Clinical Investigation, 128(5), 1919-1936. https://doi.org/10.1172/JCI91646
Varelias, Antiopi ; Bunting, Mark D. ; Ormerod, Kate L. ; Koyama, Motoko ; Olver, Stuart D. ; Straube, Jasmin ; Kuns, Rachel D. ; Robb, Renee J. ; Henden, Andrea S. ; Cooper, Leanne ; Lachner, Nancy ; Gartlan, Kate H. ; Lantz, Olivier ; Kjer-Nielsen, Lars ; Mak, Jeffrey Y.W. ; Fairlie, David P. ; Clouston, Andrew D. ; McCluskey, James ; Rossjohn, Jamie ; Lane, Steven W. ; Hugenholtz, Philip ; Hill, Geoffrey R. / Recipient mucosal-associated invariant T cells control GVHD within the colon. In: Journal of Clinical Investigation. 2018 ; Vol. 128, No. 5. pp. 1919-1936.
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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.",
author = "Antiopi Varelias and Bunting, {Mark D.} and Ormerod, {Kate L.} and Motoko Koyama and Olver, {Stuart D.} and Jasmin Straube and Kuns, {Rachel D.} and Robb, {Renee J.} and Henden, {Andrea S.} and Leanne Cooper and Nancy Lachner and Gartlan, {Kate H.} and Olivier Lantz and Lars Kjer-Nielsen and Mak, {Jeffrey Y.W.} and Fairlie, {David P.} and Clouston, {Andrew D.} and James McCluskey and Jamie Rossjohn and Lane, {Steven W.} and Philip Hugenholtz and Hill, {Geoffrey R.}",
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Varelias, A, Bunting, MD, Ormerod, KL, Koyama, M, Olver, SD, Straube, J, Kuns, RD, Robb, RJ, Henden, AS, Cooper, L, Lachner, N, Gartlan, KH, Lantz, O, Kjer-Nielsen, L, Mak, JYW, Fairlie, DP, Clouston, AD, McCluskey, J, Rossjohn, J, Lane, SW, Hugenholtz, P & Hill, GR 2018, 'Recipient mucosal-associated invariant T cells control GVHD within the colon' Journal of Clinical Investigation, vol. 128, no. 5, pp. 1919-1936. https://doi.org/10.1172/JCI91646

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

In: Journal of Clinical Investigation, Vol. 128, No. 5, 01.05.2018, p. 1919-1936.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Varelias, Antiopi

AU - Bunting, Mark D.

AU - Ormerod, Kate L.

AU - Koyama, Motoko

AU - Olver, Stuart D.

AU - Straube, Jasmin

AU - Kuns, Rachel D.

AU - Robb, Renee J.

AU - Henden, Andrea S.

AU - Cooper, Leanne

AU - Lachner, Nancy

AU - Gartlan, Kate H.

AU - Lantz, Olivier

AU - Kjer-Nielsen, Lars

AU - Mak, Jeffrey Y.W.

AU - Fairlie, David P.

AU - Clouston, Andrew D.

AU - McCluskey, James

AU - Rossjohn, Jamie

AU - Lane, Steven W.

AU - Hugenholtz, Philip

AU - Hill, Geoffrey R.

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N2 - 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.

AB - 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.

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Varelias A, Bunting MD, Ormerod KL, Koyama M, Olver SD, Straube J et al. Recipient mucosal-associated invariant T cells control GVHD within the colon. Journal of Clinical Investigation. 2018 May 1;128(5):1919-1936. https://doi.org/10.1172/JCI91646