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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...
Autores principales: | , , , , , |
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Formato: | Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2011
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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. |
format | Text |
id | pubmed-3023775 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2011 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
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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