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The activity of the aryl hydrocarbon receptor in T cells tunes the gut microenvironment to sustain autoimmunity and neuroinflammation

Multiple sclerosis (MS) is a T cell-driven autoimmune disease that attacks the myelin of the central nervous system (CNS) and currently has no cure. MS etiology is linked to both the gut flora and external environmental factors but this connection is not well understood. One immune system regulator...

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Autores principales: Merchak, Andrea R., Cahill, Hannah J., Brown, Lucille C., Brown, Ryan M., Rivet-Noor, Courtney, Beiter, Rebecca M., Slogar, Erica R., Olgun, Deniz G., Gaultier, Alban
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9928083/
https://www.ncbi.nlm.nih.gov/pubmed/36787309
http://dx.doi.org/10.1371/journal.pbio.3002000
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author Merchak, Andrea R.
Cahill, Hannah J.
Brown, Lucille C.
Brown, Ryan M.
Rivet-Noor, Courtney
Beiter, Rebecca M.
Slogar, Erica R.
Olgun, Deniz G.
Gaultier, Alban
author_facet Merchak, Andrea R.
Cahill, Hannah J.
Brown, Lucille C.
Brown, Ryan M.
Rivet-Noor, Courtney
Beiter, Rebecca M.
Slogar, Erica R.
Olgun, Deniz G.
Gaultier, Alban
author_sort Merchak, Andrea R.
collection PubMed
description Multiple sclerosis (MS) is a T cell-driven autoimmune disease that attacks the myelin of the central nervous system (CNS) and currently has no cure. MS etiology is linked to both the gut flora and external environmental factors but this connection is not well understood. One immune system regulator responsive to nonpathogenic external stimuli is the aryl hydrocarbon receptor (AHR). The AHR, which binds diverse molecules present in the environment in barrier tissues, is a therapeutic target for MS. However, AHR’s precise function in T lymphocytes, the orchestrators of MS, has not been described. Here, we show that in a mouse model of MS, T cell-specific Ahr knockout leads to recovery driven by a decrease in T cell fitness. At the mechanistic level, we demonstrate that the absence of AHR changes the gut microenvironment composition to generate metabolites that impact T cell viability, such as bile salts and short chain fatty acids. Our study demonstrates a newly emerging role for AHR in mediating the interdependence between T lymphocytes and the microbiota, while simultaneously identifying new potential molecular targets for the treatment of MS and other autoimmune diseases.
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spelling pubmed-99280832023-02-15 The activity of the aryl hydrocarbon receptor in T cells tunes the gut microenvironment to sustain autoimmunity and neuroinflammation Merchak, Andrea R. Cahill, Hannah J. Brown, Lucille C. Brown, Ryan M. Rivet-Noor, Courtney Beiter, Rebecca M. Slogar, Erica R. Olgun, Deniz G. Gaultier, Alban PLoS Biol Research Article Multiple sclerosis (MS) is a T cell-driven autoimmune disease that attacks the myelin of the central nervous system (CNS) and currently has no cure. MS etiology is linked to both the gut flora and external environmental factors but this connection is not well understood. One immune system regulator responsive to nonpathogenic external stimuli is the aryl hydrocarbon receptor (AHR). The AHR, which binds diverse molecules present in the environment in barrier tissues, is a therapeutic target for MS. However, AHR’s precise function in T lymphocytes, the orchestrators of MS, has not been described. Here, we show that in a mouse model of MS, T cell-specific Ahr knockout leads to recovery driven by a decrease in T cell fitness. At the mechanistic level, we demonstrate that the absence of AHR changes the gut microenvironment composition to generate metabolites that impact T cell viability, such as bile salts and short chain fatty acids. Our study demonstrates a newly emerging role for AHR in mediating the interdependence between T lymphocytes and the microbiota, while simultaneously identifying new potential molecular targets for the treatment of MS and other autoimmune diseases. Public Library of Science 2023-02-14 /pmc/articles/PMC9928083/ /pubmed/36787309 http://dx.doi.org/10.1371/journal.pbio.3002000 Text en © 2023 Merchak et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Merchak, Andrea R.
Cahill, Hannah J.
Brown, Lucille C.
Brown, Ryan M.
Rivet-Noor, Courtney
Beiter, Rebecca M.
Slogar, Erica R.
Olgun, Deniz G.
Gaultier, Alban
The activity of the aryl hydrocarbon receptor in T cells tunes the gut microenvironment to sustain autoimmunity and neuroinflammation
title The activity of the aryl hydrocarbon receptor in T cells tunes the gut microenvironment to sustain autoimmunity and neuroinflammation
title_full The activity of the aryl hydrocarbon receptor in T cells tunes the gut microenvironment to sustain autoimmunity and neuroinflammation
title_fullStr The activity of the aryl hydrocarbon receptor in T cells tunes the gut microenvironment to sustain autoimmunity and neuroinflammation
title_full_unstemmed The activity of the aryl hydrocarbon receptor in T cells tunes the gut microenvironment to sustain autoimmunity and neuroinflammation
title_short The activity of the aryl hydrocarbon receptor in T cells tunes the gut microenvironment to sustain autoimmunity and neuroinflammation
title_sort activity of the aryl hydrocarbon receptor in t cells tunes the gut microenvironment to sustain autoimmunity and neuroinflammation
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9928083/
https://www.ncbi.nlm.nih.gov/pubmed/36787309
http://dx.doi.org/10.1371/journal.pbio.3002000
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