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Thymic negative selection is functional in NOD mice
Based on analyses of multiple TCR transgenic (tg) models, the emergence of pathogenic T cells in diabetes-prone NOD mice has been ascribed to a failure to censure autoreactive clones in the thymus. In contrast, using isolated and preselected thymocytes, we show that nonobese diabetic (NOD) genetic v...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The Rockefeller University Press
2012
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3302233/ https://www.ncbi.nlm.nih.gov/pubmed/22329992 http://dx.doi.org/10.1084/jem.20112593 |
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author | Mingueneau, Michael Jiang, Wenyu Feuerer, Markus Mathis, Diane Benoist, Christophe |
author_facet | Mingueneau, Michael Jiang, Wenyu Feuerer, Markus Mathis, Diane Benoist, Christophe |
author_sort | Mingueneau, Michael |
collection | PubMed |
description | Based on analyses of multiple TCR transgenic (tg) models, the emergence of pathogenic T cells in diabetes-prone NOD mice has been ascribed to a failure to censure autoreactive clones in the thymus. In contrast, using isolated and preselected thymocytes, we show that nonobese diabetic (NOD) genetic variation impairs neither clonal deletion nor downstream transcriptional programs. However, we find that NOD genetic variation influences αβ/γδ-lineage decisions promoted by early expression of tg αβ-TCRs at the double-negative (DN) stage. In B6 and other genetic backgrounds, tg αβ-TCRs behave like γδ-TCRs and commit a large fraction of DNs toward the γδ-lineage, thereby decreasing the size of the double-positive (DP) pool, which is efficiently positively and negatively selected. In NOD DNs, αβ-TCR signalosomes instead behave like pre-TCRs, resulting in high numbers of DPs competing for limited selection niches, and poor positive and negative selection. Once niche effects are neutralized in mixed bone marrow chimeras, positive and negative selection are equally efficient on B6 and NOD backgrounds. Biochemical analysis revealed a selective defect in the activation of Erk1/2 downstream of NOD αβ-TCR signalosomes. Therefore, NOD genetic variation influences αβ/γδ-lineage decisions when the αβ-TCR heterodimer is prematurely expressed, but not the process of negative selection. |
format | Online Article Text |
id | pubmed-3302233 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | The Rockefeller University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-33022332012-09-12 Thymic negative selection is functional in NOD mice Mingueneau, Michael Jiang, Wenyu Feuerer, Markus Mathis, Diane Benoist, Christophe J Exp Med Article Based on analyses of multiple TCR transgenic (tg) models, the emergence of pathogenic T cells in diabetes-prone NOD mice has been ascribed to a failure to censure autoreactive clones in the thymus. In contrast, using isolated and preselected thymocytes, we show that nonobese diabetic (NOD) genetic variation impairs neither clonal deletion nor downstream transcriptional programs. However, we find that NOD genetic variation influences αβ/γδ-lineage decisions promoted by early expression of tg αβ-TCRs at the double-negative (DN) stage. In B6 and other genetic backgrounds, tg αβ-TCRs behave like γδ-TCRs and commit a large fraction of DNs toward the γδ-lineage, thereby decreasing the size of the double-positive (DP) pool, which is efficiently positively and negatively selected. In NOD DNs, αβ-TCR signalosomes instead behave like pre-TCRs, resulting in high numbers of DPs competing for limited selection niches, and poor positive and negative selection. Once niche effects are neutralized in mixed bone marrow chimeras, positive and negative selection are equally efficient on B6 and NOD backgrounds. Biochemical analysis revealed a selective defect in the activation of Erk1/2 downstream of NOD αβ-TCR signalosomes. Therefore, NOD genetic variation influences αβ/γδ-lineage decisions when the αβ-TCR heterodimer is prematurely expressed, but not the process of negative selection. The Rockefeller University Press 2012-03-12 /pmc/articles/PMC3302233/ /pubmed/22329992 http://dx.doi.org/10.1084/jem.20112593 Text en © 2012 Mingueneau et al. 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 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/). |
spellingShingle | Article Mingueneau, Michael Jiang, Wenyu Feuerer, Markus Mathis, Diane Benoist, Christophe Thymic negative selection is functional in NOD mice |
title | Thymic negative selection is functional in NOD mice |
title_full | Thymic negative selection is functional in NOD mice |
title_fullStr | Thymic negative selection is functional in NOD mice |
title_full_unstemmed | Thymic negative selection is functional in NOD mice |
title_short | Thymic negative selection is functional in NOD mice |
title_sort | thymic negative selection is functional in nod mice |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3302233/ https://www.ncbi.nlm.nih.gov/pubmed/22329992 http://dx.doi.org/10.1084/jem.20112593 |
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