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Avidity-Dependent Programming of Autoreactive T Cells in T1D
Fate determination for autoreactive T cells relies on a series of avidity-dependent interactions during T cell selection, represented by two general types of signals, one based on antigen expression and density during T cell development, and one based on genes that interpret the avidity of TCR inter...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4028311/ https://www.ncbi.nlm.nih.gov/pubmed/24844227 http://dx.doi.org/10.1371/journal.pone.0098074 |
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author | Durinovic-Belló, Ivana Gersuk, Vivian H. Ni, Chester Wu, Rebecca Thorpe, Jerill Jospe, Nicholas Sanda, Srinath Greenbaum, Carla J. Nepom, Gerald T. |
author_facet | Durinovic-Belló, Ivana Gersuk, Vivian H. Ni, Chester Wu, Rebecca Thorpe, Jerill Jospe, Nicholas Sanda, Srinath Greenbaum, Carla J. Nepom, Gerald T. |
author_sort | Durinovic-Belló, Ivana |
collection | PubMed |
description | Fate determination for autoreactive T cells relies on a series of avidity-dependent interactions during T cell selection, represented by two general types of signals, one based on antigen expression and density during T cell development, and one based on genes that interpret the avidity of TCR interaction to guide developmental outcome. We used proinsulin-specific HLA class II tetramers to purify and determine transcriptional signatures for autoreactive T cells under differential selection in type 1 diabetes (T1D), in which insulin (INS) genotypes consist of protective and susceptible alleles that regulate the level of proinsulin expression in the thymus. Upregulation of steroid nuclear receptor family 4A (NR4A) and early growth response family genes in proinsulin-specific T cells was observed in individuals with susceptible INS-VNTR genotypes, suggesting a mechanism for avidity-dependent fate determination of the T cell repertoire in T1D. The NR4A genes act as translators of TCR signal strength that guide central and peripheral T cell fate decisions through transcriptional modification. We propose that maintenance of an NR4A-guided program in low avidity autoreactive T cells in T1D reflects their prior developmental experience influenced by proinsulin expression, identifying a pathway permissive for autoimmunity. |
format | Online Article Text |
id | pubmed-4028311 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-40283112014-05-21 Avidity-Dependent Programming of Autoreactive T Cells in T1D Durinovic-Belló, Ivana Gersuk, Vivian H. Ni, Chester Wu, Rebecca Thorpe, Jerill Jospe, Nicholas Sanda, Srinath Greenbaum, Carla J. Nepom, Gerald T. PLoS One Research Article Fate determination for autoreactive T cells relies on a series of avidity-dependent interactions during T cell selection, represented by two general types of signals, one based on antigen expression and density during T cell development, and one based on genes that interpret the avidity of TCR interaction to guide developmental outcome. We used proinsulin-specific HLA class II tetramers to purify and determine transcriptional signatures for autoreactive T cells under differential selection in type 1 diabetes (T1D), in which insulin (INS) genotypes consist of protective and susceptible alleles that regulate the level of proinsulin expression in the thymus. Upregulation of steroid nuclear receptor family 4A (NR4A) and early growth response family genes in proinsulin-specific T cells was observed in individuals with susceptible INS-VNTR genotypes, suggesting a mechanism for avidity-dependent fate determination of the T cell repertoire in T1D. The NR4A genes act as translators of TCR signal strength that guide central and peripheral T cell fate decisions through transcriptional modification. We propose that maintenance of an NR4A-guided program in low avidity autoreactive T cells in T1D reflects their prior developmental experience influenced by proinsulin expression, identifying a pathway permissive for autoimmunity. Public Library of Science 2014-05-20 /pmc/articles/PMC4028311/ /pubmed/24844227 http://dx.doi.org/10.1371/journal.pone.0098074 Text en © 2014 Durinovic-Belló 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 Durinovic-Belló, Ivana Gersuk, Vivian H. Ni, Chester Wu, Rebecca Thorpe, Jerill Jospe, Nicholas Sanda, Srinath Greenbaum, Carla J. Nepom, Gerald T. Avidity-Dependent Programming of Autoreactive T Cells in T1D |
title | Avidity-Dependent Programming of Autoreactive T Cells in T1D |
title_full | Avidity-Dependent Programming of Autoreactive T Cells in T1D |
title_fullStr | Avidity-Dependent Programming of Autoreactive T Cells in T1D |
title_full_unstemmed | Avidity-Dependent Programming of Autoreactive T Cells in T1D |
title_short | Avidity-Dependent Programming of Autoreactive T Cells in T1D |
title_sort | avidity-dependent programming of autoreactive t cells in t1d |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4028311/ https://www.ncbi.nlm.nih.gov/pubmed/24844227 http://dx.doi.org/10.1371/journal.pone.0098074 |
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