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Dynamic changes in E-protein activity regulate T reg cell development
E-proteins are TCR-sensitive transcription factors essential for intrathymic T cell transitions. Here, we show that deletion of E-proteins leads to both enhanced peripheral TGF-β–induced regulatory T (iT reg) cell and thymic naturally arising T reg cell (nT reg cell) differentiation. In contrast, de...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The Rockefeller University Press
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4267236/ https://www.ncbi.nlm.nih.gov/pubmed/25488982 http://dx.doi.org/10.1084/jem.20132681 |
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author | Gao, Ping Han, Xiaojuan Zhang, Qi Yang, Zhiqiong Fuss, Ivan J. Myers, Timothy G. Gardina, Paul J. Zhang, Fuping Strober, Warren |
author_facet | Gao, Ping Han, Xiaojuan Zhang, Qi Yang, Zhiqiong Fuss, Ivan J. Myers, Timothy G. Gardina, Paul J. Zhang, Fuping Strober, Warren |
author_sort | Gao, Ping |
collection | PubMed |
description | E-proteins are TCR-sensitive transcription factors essential for intrathymic T cell transitions. Here, we show that deletion of E-proteins leads to both enhanced peripheral TGF-β–induced regulatory T (iT reg) cell and thymic naturally arising T reg cell (nT reg cell) differentiation. In contrast, deletion of Id proteins results in reduced nT reg cell differentiation. Mechanistic analysis indicated that decreased E-protein activity leads to de-repression of signaling pathways that are essential to Foxp3 expression. Decreased E-protein binding to an IL-2Rα enhancer locus facilitated TCR-induced IL-2Rα expression. Similarly, decreased E-protein activity facilitated TCR-induced NF-κB activation and generation of c-Rel. Consistent with this, microarray analysis indicated that cells with E-protein depletion that are not yet expressing Foxp3 exhibit activation of the IL-2 and NF-κB signaling pathways as well as enhanced expression of many of the genes associated with Foxp3 induction. Finally, studies using Nur77-GFP mice to monitor TCR signaling showed that TCR signaling strength sufficient to induce Foxp3 differentiation is accompanied by down-regulation of E-protein levels. Collectively, these data suggest that TCR stimulation acts in part through down-regulation of E-protein activity to induce T reg cell lineage development. |
format | Online Article Text |
id | pubmed-4267236 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | The Rockefeller University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-42672362015-06-15 Dynamic changes in E-protein activity regulate T reg cell development Gao, Ping Han, Xiaojuan Zhang, Qi Yang, Zhiqiong Fuss, Ivan J. Myers, Timothy G. Gardina, Paul J. Zhang, Fuping Strober, Warren J Exp Med Article E-proteins are TCR-sensitive transcription factors essential for intrathymic T cell transitions. Here, we show that deletion of E-proteins leads to both enhanced peripheral TGF-β–induced regulatory T (iT reg) cell and thymic naturally arising T reg cell (nT reg cell) differentiation. In contrast, deletion of Id proteins results in reduced nT reg cell differentiation. Mechanistic analysis indicated that decreased E-protein activity leads to de-repression of signaling pathways that are essential to Foxp3 expression. Decreased E-protein binding to an IL-2Rα enhancer locus facilitated TCR-induced IL-2Rα expression. Similarly, decreased E-protein activity facilitated TCR-induced NF-κB activation and generation of c-Rel. Consistent with this, microarray analysis indicated that cells with E-protein depletion that are not yet expressing Foxp3 exhibit activation of the IL-2 and NF-κB signaling pathways as well as enhanced expression of many of the genes associated with Foxp3 induction. Finally, studies using Nur77-GFP mice to monitor TCR signaling showed that TCR signaling strength sufficient to induce Foxp3 differentiation is accompanied by down-regulation of E-protein levels. Collectively, these data suggest that TCR stimulation acts in part through down-regulation of E-protein activity to induce T reg cell lineage development. The Rockefeller University Press 2014-12-15 /pmc/articles/PMC4267236/ /pubmed/25488982 http://dx.doi.org/10.1084/jem.20132681 Text en © 2014 Gao 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 Gao, Ping Han, Xiaojuan Zhang, Qi Yang, Zhiqiong Fuss, Ivan J. Myers, Timothy G. Gardina, Paul J. Zhang, Fuping Strober, Warren Dynamic changes in E-protein activity regulate T reg cell development |
title | Dynamic changes in E-protein activity regulate T reg cell development |
title_full | Dynamic changes in E-protein activity regulate T reg cell development |
title_fullStr | Dynamic changes in E-protein activity regulate T reg cell development |
title_full_unstemmed | Dynamic changes in E-protein activity regulate T reg cell development |
title_short | Dynamic changes in E-protein activity regulate T reg cell development |
title_sort | dynamic changes in e-protein activity regulate t reg cell development |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4267236/ https://www.ncbi.nlm.nih.gov/pubmed/25488982 http://dx.doi.org/10.1084/jem.20132681 |
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