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Inhibition of Nur77/Nurr1 leads to inefficient clonal deletion of self- reactive T cells
The Nur77/Nurr1 family of DNA binding proteins has been reported to be required for the signal transduction of CD3/T cell receptor (TCR)- mediated apoptosis in T cell hybridomas. To determine the role of this family of DNA-binding proteins in thymic clonal deletion, transgenic (Tg) mice bearing a do...
Formato: | Texto |
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Lenguaje: | English |
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The Rockefeller University Press
1996
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2192482/ https://www.ncbi.nlm.nih.gov/pubmed/8666944 |
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collection | PubMed |
description | The Nur77/Nurr1 family of DNA binding proteins has been reported to be required for the signal transduction of CD3/T cell receptor (TCR)- mediated apoptosis in T cell hybridomas. To determine the role of this family of DNA-binding proteins in thymic clonal deletion, transgenic (Tg) mice bearing a dominant negative mutation were produced. The transgene consisted of a truncated Nur77 (deltaNur77) gene encoding the DNA-binding domain of Nur77 ligated to a TCR-beta enhancer resulting in early expression in thymocytes. Apoptosis of CD4+CD8+ thymocytes mediated by CD3/TCR signaling was greatly inhibited in the deltaNur77 Tg mice, compared with non-Tg littermates, after treatment with anti- CD3 or anti-TCR antibody in vivo and in vitro. Clonal deletion of self- reactive T cells was investigated in deltaNur77-Db/HY TCR-alpha/beta double Tg mice. There was a five-fold increase in the total number of thymocytes expressing self-reactive Db/HY TCR-alpha/beta in the deltaNur77-TCR-alpha/beta double Tg male mice. Deficient clonal deletion of self-reactive thymocytes was demonstrated by a 10-fold increase in the CD4+CD8+ thymocytes that expressed Tg TCR-alpha/beta. There was an eightfold increase in the CD8+, Db/HY TCR-alpha/beta T cells in the lymph nodes (LN) of delta Nur77-Db/HY TCR-alpha/beta double Tg compared with Db/HY TCR-alpha/beta Tg male mice. In spite of defective clonal deletion, the T cells expressing the Tg TCR were functionally anergic. In vivo analysis revealed increased activation and apoptosis of T cells associated with increased expression of Fas and Fas ligand in LN of deltaNur77-Db/HY TCR-alpha/beta double male mice. These results indicate that inhibition of Nur77/Nurr1 DNA binding in T cells leads to inefficient thymic clonal deletion, but T cell tolerance is maintained by Fas-dependent clonal deletion in LN and spleen. |
format | Text |
id | pubmed-2192482 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 1996 |
publisher | The Rockefeller University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-21924822008-04-16 Inhibition of Nur77/Nurr1 leads to inefficient clonal deletion of self- reactive T cells J Exp Med Articles The Nur77/Nurr1 family of DNA binding proteins has been reported to be required for the signal transduction of CD3/T cell receptor (TCR)- mediated apoptosis in T cell hybridomas. To determine the role of this family of DNA-binding proteins in thymic clonal deletion, transgenic (Tg) mice bearing a dominant negative mutation were produced. The transgene consisted of a truncated Nur77 (deltaNur77) gene encoding the DNA-binding domain of Nur77 ligated to a TCR-beta enhancer resulting in early expression in thymocytes. Apoptosis of CD4+CD8+ thymocytes mediated by CD3/TCR signaling was greatly inhibited in the deltaNur77 Tg mice, compared with non-Tg littermates, after treatment with anti- CD3 or anti-TCR antibody in vivo and in vitro. Clonal deletion of self- reactive T cells was investigated in deltaNur77-Db/HY TCR-alpha/beta double Tg mice. There was a five-fold increase in the total number of thymocytes expressing self-reactive Db/HY TCR-alpha/beta in the deltaNur77-TCR-alpha/beta double Tg male mice. Deficient clonal deletion of self-reactive thymocytes was demonstrated by a 10-fold increase in the CD4+CD8+ thymocytes that expressed Tg TCR-alpha/beta. There was an eightfold increase in the CD8+, Db/HY TCR-alpha/beta T cells in the lymph nodes (LN) of delta Nur77-Db/HY TCR-alpha/beta double Tg compared with Db/HY TCR-alpha/beta Tg male mice. In spite of defective clonal deletion, the T cells expressing the Tg TCR were functionally anergic. In vivo analysis revealed increased activation and apoptosis of T cells associated with increased expression of Fas and Fas ligand in LN of deltaNur77-Db/HY TCR-alpha/beta double male mice. These results indicate that inhibition of Nur77/Nurr1 DNA binding in T cells leads to inefficient thymic clonal deletion, but T cell tolerance is maintained by Fas-dependent clonal deletion in LN and spleen. The Rockefeller University Press 1996-04-01 /pmc/articles/PMC2192482/ /pubmed/8666944 Text en 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 4.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/4.0/). |
spellingShingle | Articles Inhibition of Nur77/Nurr1 leads to inefficient clonal deletion of self- reactive T cells |
title | Inhibition of Nur77/Nurr1 leads to inefficient clonal deletion of self- reactive T cells |
title_full | Inhibition of Nur77/Nurr1 leads to inefficient clonal deletion of self- reactive T cells |
title_fullStr | Inhibition of Nur77/Nurr1 leads to inefficient clonal deletion of self- reactive T cells |
title_full_unstemmed | Inhibition of Nur77/Nurr1 leads to inefficient clonal deletion of self- reactive T cells |
title_short | Inhibition of Nur77/Nurr1 leads to inefficient clonal deletion of self- reactive T cells |
title_sort | inhibition of nur77/nurr1 leads to inefficient clonal deletion of self- reactive t cells |
topic | Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2192482/ https://www.ncbi.nlm.nih.gov/pubmed/8666944 |