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BCAP links IL-1R to the PI3K–mTOR pathway and regulates pathogenic Th17 cell differentiation

The toll-like receptor (TLR) and interleukin (IL)–1 family of receptors share several signaling components, including the most upstream adapter, MyD88. We previously reported the discovery of B cell adapter for phosphoinositide 3-kinase (BCAP) as a novel toll–IL-1 receptor homology domain–containing...

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Autores principales: Deason, Krystin, Troutman, Ty Dale, Jain, Aakanksha, Challa, Dilip K., Mandraju, Rajakumar, Brewer, Travis, Ward, E. Sally, Pasare, Chandrashekhar
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Rockefeller University Press 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6122979/
https://www.ncbi.nlm.nih.gov/pubmed/30093533
http://dx.doi.org/10.1084/jem.20171810
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author Deason, Krystin
Troutman, Ty Dale
Jain, Aakanksha
Challa, Dilip K.
Mandraju, Rajakumar
Brewer, Travis
Ward, E. Sally
Pasare, Chandrashekhar
author_facet Deason, Krystin
Troutman, Ty Dale
Jain, Aakanksha
Challa, Dilip K.
Mandraju, Rajakumar
Brewer, Travis
Ward, E. Sally
Pasare, Chandrashekhar
author_sort Deason, Krystin
collection PubMed
description The toll-like receptor (TLR) and interleukin (IL)–1 family of receptors share several signaling components, including the most upstream adapter, MyD88. We previously reported the discovery of B cell adapter for phosphoinositide 3-kinase (BCAP) as a novel toll–IL-1 receptor homology domain–containing adapter that regulates inflammatory responses downstream of TLR signaling. Here we find that BCAP plays a critical role downstream of both IL-1 and IL-18 receptors to regulate T helper (Th) 17 and Th1 cell differentiation, respectively. Absence of T cell intrinsic BCAP did not alter development of naturally arising Th1 and Th17 lineages but led to defects in differentiation to pathogenic Th17 lineage cells. Consequently, mice that lack BCAP in T cells had reduced susceptibility to experimental autoimmune encephalomyelitis. More importantly, we found that BCAP is critical for IL-1R–induced phosphoinositide 3-kinase–Akt–mechanistic target of rapamycin (mTOR) activation, and minimal inhibition of mTOR completely abrogated IL-1β–induced differentiation of pathogenic Th17 cells, mimicking BCAP deficiency. This study establishes BCAP as a critical link between IL-1R and the metabolic status of activated T cells that ultimately regulates the differentiation of inflammatory Th17 cells.
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spelling pubmed-61229792019-03-03 BCAP links IL-1R to the PI3K–mTOR pathway and regulates pathogenic Th17 cell differentiation Deason, Krystin Troutman, Ty Dale Jain, Aakanksha Challa, Dilip K. Mandraju, Rajakumar Brewer, Travis Ward, E. Sally Pasare, Chandrashekhar J Exp Med Research Articles The toll-like receptor (TLR) and interleukin (IL)–1 family of receptors share several signaling components, including the most upstream adapter, MyD88. We previously reported the discovery of B cell adapter for phosphoinositide 3-kinase (BCAP) as a novel toll–IL-1 receptor homology domain–containing adapter that regulates inflammatory responses downstream of TLR signaling. Here we find that BCAP plays a critical role downstream of both IL-1 and IL-18 receptors to regulate T helper (Th) 17 and Th1 cell differentiation, respectively. Absence of T cell intrinsic BCAP did not alter development of naturally arising Th1 and Th17 lineages but led to defects in differentiation to pathogenic Th17 lineage cells. Consequently, mice that lack BCAP in T cells had reduced susceptibility to experimental autoimmune encephalomyelitis. More importantly, we found that BCAP is critical for IL-1R–induced phosphoinositide 3-kinase–Akt–mechanistic target of rapamycin (mTOR) activation, and minimal inhibition of mTOR completely abrogated IL-1β–induced differentiation of pathogenic Th17 cells, mimicking BCAP deficiency. This study establishes BCAP as a critical link between IL-1R and the metabolic status of activated T cells that ultimately regulates the differentiation of inflammatory Th17 cells. Rockefeller University Press 2018-09-03 /pmc/articles/PMC6122979/ /pubmed/30093533 http://dx.doi.org/10.1084/jem.20171810 Text en © 2018 Deason et al. http://www.rupress.org/terms/https://creativecommons.org/licenses/by-nc-sa/4.0/This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
spellingShingle Research Articles
Deason, Krystin
Troutman, Ty Dale
Jain, Aakanksha
Challa, Dilip K.
Mandraju, Rajakumar
Brewer, Travis
Ward, E. Sally
Pasare, Chandrashekhar
BCAP links IL-1R to the PI3K–mTOR pathway and regulates pathogenic Th17 cell differentiation
title BCAP links IL-1R to the PI3K–mTOR pathway and regulates pathogenic Th17 cell differentiation
title_full BCAP links IL-1R to the PI3K–mTOR pathway and regulates pathogenic Th17 cell differentiation
title_fullStr BCAP links IL-1R to the PI3K–mTOR pathway and regulates pathogenic Th17 cell differentiation
title_full_unstemmed BCAP links IL-1R to the PI3K–mTOR pathway and regulates pathogenic Th17 cell differentiation
title_short BCAP links IL-1R to the PI3K–mTOR pathway and regulates pathogenic Th17 cell differentiation
title_sort bcap links il-1r to the pi3k–mtor pathway and regulates pathogenic th17 cell differentiation
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6122979/
https://www.ncbi.nlm.nih.gov/pubmed/30093533
http://dx.doi.org/10.1084/jem.20171810
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