The dynamic processing of CD46 intracellular domains provides a molecular rheostat for T cell activation.
<h4>Background</h4>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 defe...
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| Language: | English |
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Public Library of Science (PLoS)
2011-01-01
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| Series: | PLoS ONE |
| Online Access: | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0016287&type=printable |
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| author | Siobhan Ni Choileain Nathan J Weyand Christian Neumann Joelle Thomas Magdalene So Anne L Astier |
| author_facet | Siobhan Ni Choileain Nathan J Weyand Christian Neumann Joelle Thomas Magdalene So Anne L Astier |
| author_sort | Siobhan Ni Choileain |
| collection | DOAJ |
| description | <h4>Background</h4>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.<h4>Methodology/principal findings</h4>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.<h4>Conclusions/significance</h4>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 | Article |
| id | doaj-art-e596eeb0f7994e5387ffe1741e776b89 |
| institution | OA Journals |
| issn | 1932-6203 |
| language | English |
| publishDate | 2011-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj-art-e596eeb0f7994e5387ffe1741e776b892025-08-20T02:34:16ZengPublic Library of Science (PLoS)PLoS ONE1932-62032011-01-0161e1628710.1371/journal.pone.0016287The dynamic processing of CD46 intracellular domains provides a molecular rheostat for T cell activation.Siobhan Ni ChoileainNathan J WeyandChristian NeumannJoelle ThomasMagdalene SoAnne L Astier<h4>Background</h4>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.<h4>Methodology/principal findings</h4>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.<h4>Conclusions/significance</h4>We conclude that CD46 acts as a molecular rheostat to control human T cell activation through the regulation of processing of its cytoplasmic tails.https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0016287&type=printable |
| spellingShingle | Siobhan Ni Choileain Nathan J Weyand Christian Neumann Joelle Thomas Magdalene So Anne L Astier The dynamic processing of CD46 intracellular domains provides a molecular rheostat for T cell activation. PLoS ONE |
| 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 |
| url | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0016287&type=printable |
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