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The Dynamic Processing of CD46 Intracellular Domains Provides a Molecular Rheostat for T Cell Activation

BACKGROUND: Adequate termination of an immune response is as important as the induction of an appropriate response. CD46, a regulator of complement activity, promotes T cell activation and differentiation towards a regulatory Tr1 phenotype. This Tr1 differentiation pathway is defective in patients w...

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Autores principales: Ni Choileain, Siobhan, Weyand, Nathan J., Neumann, Christian, Thomas, Joelle, So, Magdalene, Astier, Anne L.
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3023775/
https://www.ncbi.nlm.nih.gov/pubmed/21283821
http://dx.doi.org/10.1371/journal.pone.0016287
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author Ni Choileain, Siobhan
Weyand, Nathan J.
Neumann, Christian
Thomas, Joelle
So, Magdalene
Astier, Anne L.
author_facet Ni Choileain, Siobhan
Weyand, Nathan J.
Neumann, Christian
Thomas, Joelle
So, Magdalene
Astier, Anne L.
author_sort Ni Choileain, Siobhan
collection PubMed
description BACKGROUND: Adequate termination of an immune response is as important as the induction of an appropriate response. CD46, a regulator of complement activity, promotes T cell activation and differentiation towards a regulatory Tr1 phenotype. This Tr1 differentiation pathway is defective in patients with MS, asthma and rheumatoid arthritis, underlying its importance in controlling T cell function and the need to understand its regulatory mechanisms. CD46 has two cytoplasmic tails, Cyt1 and Cyt2, derived from alternative splicing, which are co-expressed in all nucleated human cells. The regulation of their expression and precise functions in regulating human T cell activation has not been fully elucidated. METHODOLOGY/PRINCIPAL FINDINGS: Here, we first report the novel role of CD46 in terminating T cell activation. Second, we demonstrate that its functions as an activator and inhibitor of T cell responses are mediated through the temporal processing of its cytoplasmic tails. Cyt1 processing is required to turn T cell activation on, while processing of Cyt2 switches T cell activation off, as demonstrated by proliferation, CD25 expression and cytokine secretion. Both tails require processing by Presenilin/γSecretase (P/γS) to exert these functions. This was confirmed by expressing wild-type Cyt1 and Cyt2 tails and uncleavable mutant tails in primary T cells. The role of CD46 tails was also demonstrated with T cells expressing CD19 ectodomain-CD46 C-Terminal Fragment (CTF) fusions, which allowed specific triggering of each tail individually. CONCLUSIONS/SIGNIFICANCE: We conclude that CD46 acts as a molecular rheostat to control human T cell activation through the regulation of processing of its cytoplasmic tails.
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spelling pubmed-30237752011-01-31 The Dynamic Processing of CD46 Intracellular Domains Provides a Molecular Rheostat for T Cell Activation Ni Choileain, Siobhan Weyand, Nathan J. Neumann, Christian Thomas, Joelle So, Magdalene Astier, Anne L. PLoS One Research Article BACKGROUND: Adequate termination of an immune response is as important as the induction of an appropriate response. CD46, a regulator of complement activity, promotes T cell activation and differentiation towards a regulatory Tr1 phenotype. This Tr1 differentiation pathway is defective in patients with MS, asthma and rheumatoid arthritis, underlying its importance in controlling T cell function and the need to understand its regulatory mechanisms. CD46 has two cytoplasmic tails, Cyt1 and Cyt2, derived from alternative splicing, which are co-expressed in all nucleated human cells. The regulation of their expression and precise functions in regulating human T cell activation has not been fully elucidated. METHODOLOGY/PRINCIPAL FINDINGS: Here, we first report the novel role of CD46 in terminating T cell activation. Second, we demonstrate that its functions as an activator and inhibitor of T cell responses are mediated through the temporal processing of its cytoplasmic tails. Cyt1 processing is required to turn T cell activation on, while processing of Cyt2 switches T cell activation off, as demonstrated by proliferation, CD25 expression and cytokine secretion. Both tails require processing by Presenilin/γSecretase (P/γS) to exert these functions. This was confirmed by expressing wild-type Cyt1 and Cyt2 tails and uncleavable mutant tails in primary T cells. The role of CD46 tails was also demonstrated with T cells expressing CD19 ectodomain-CD46 C-Terminal Fragment (CTF) fusions, which allowed specific triggering of each tail individually. CONCLUSIONS/SIGNIFICANCE: We conclude that CD46 acts as a molecular rheostat to control human T cell activation through the regulation of processing of its cytoplasmic tails. Public Library of Science 2011-01-19 /pmc/articles/PMC3023775/ /pubmed/21283821 http://dx.doi.org/10.1371/journal.pone.0016287 Text en Ni Choileain et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Ni Choileain, Siobhan
Weyand, Nathan J.
Neumann, Christian
Thomas, Joelle
So, Magdalene
Astier, Anne L.
The Dynamic Processing of CD46 Intracellular Domains Provides a Molecular Rheostat for T Cell Activation
title The Dynamic Processing of CD46 Intracellular Domains Provides a Molecular Rheostat for T Cell Activation
title_full The Dynamic Processing of CD46 Intracellular Domains Provides a Molecular Rheostat for T Cell Activation
title_fullStr The Dynamic Processing of CD46 Intracellular Domains Provides a Molecular Rheostat for T Cell Activation
title_full_unstemmed The Dynamic Processing of CD46 Intracellular Domains Provides a Molecular Rheostat for T Cell Activation
title_short The Dynamic Processing of CD46 Intracellular Domains Provides a Molecular Rheostat for T Cell Activation
title_sort dynamic processing of cd46 intracellular domains provides a molecular rheostat for t cell activation
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3023775/
https://www.ncbi.nlm.nih.gov/pubmed/21283821
http://dx.doi.org/10.1371/journal.pone.0016287
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