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A Spontaneous Mutation of the Rat Themis Gene Leads to Impaired Function of Regulatory T Cells Linked to Inflammatory Bowel Disease
Spontaneous or chemically induced germline mutations, which lead to Mendelian phenotypes, are powerful tools to discover new genes and their functions. Here, we report an autosomal recessive mutation that occurred spontaneously in a Brown-Norway (BN) rat colony and was identified as causing marked T...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2012
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3261907/ https://www.ncbi.nlm.nih.gov/pubmed/22275874 http://dx.doi.org/10.1371/journal.pgen.1002461 |
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author | Chabod, Marianne Pedros, Christophe Lamouroux, Lucille Colacios, Céline Bernard, Isabelle Lagrange, Dominique Balz-Hara, Daniela Mosnier, Jean-Francois Laboisse, Christian Vergnolle, Nathalie Andreoletti, Olivier Roth, Marie-Paule Liblau, Roland Fournié, Gilbert J. Saoudi, Abdelhadi Dejean, Anne S. |
author_facet | Chabod, Marianne Pedros, Christophe Lamouroux, Lucille Colacios, Céline Bernard, Isabelle Lagrange, Dominique Balz-Hara, Daniela Mosnier, Jean-Francois Laboisse, Christian Vergnolle, Nathalie Andreoletti, Olivier Roth, Marie-Paule Liblau, Roland Fournié, Gilbert J. Saoudi, Abdelhadi Dejean, Anne S. |
author_sort | Chabod, Marianne |
collection | PubMed |
description | Spontaneous or chemically induced germline mutations, which lead to Mendelian phenotypes, are powerful tools to discover new genes and their functions. Here, we report an autosomal recessive mutation that occurred spontaneously in a Brown-Norway (BN) rat colony and was identified as causing marked T cell lymphopenia. This mutation was stabilized in a new rat strain, named BN(m) for “BN mutated.” In BN(m) rats, we found that the T cell lymphopenia originated in the thymus, was intrinsic to CD4 T lymphocytes, and was associated with the development of an inflammatory bowel disease. Furthermore, we demonstrate that the suppressive activity of both peripheral and thymic CD4(+) CD25(bright) regulatory T cells (Treg) is defective in BN(m) rats. Complementation of mutant animals with BN Treg decreases disease incidence and severity, thus suggesting that the impaired Treg function is involved in the development of inflammatory bowel disease in BN(m) rats. Moreover, the cytokine profile of effector CD4 T cells is skewed toward Th2 and Th17 phenotypes in BN(m) rats. Linkage analysis and genetic dissection of the CD4 T cell lymphopenia in rats issued from BN(m)×DA crosses allowed the localization of the mutation on chromosome 1, within a 1.5 megabase interval. Gene expression and sequencing studies identified a frameshift mutation caused by a four-nucleotide insertion in the Themis gene, leading to its disruption. This result is the first to link Themis to the suppressive function of Treg and to suggest that, in Themis-deficient animals, defect of this function is involved in intestinal inflammation. Thus, this study highlights the importance of Themis as a new target gene that could participate in the pathogenesis of immune diseases characterized by chronic inflammation resulting from a defect in the Treg compartment. |
format | Online Article Text |
id | pubmed-3261907 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-32619072012-01-24 A Spontaneous Mutation of the Rat Themis Gene Leads to Impaired Function of Regulatory T Cells Linked to Inflammatory Bowel Disease Chabod, Marianne Pedros, Christophe Lamouroux, Lucille Colacios, Céline Bernard, Isabelle Lagrange, Dominique Balz-Hara, Daniela Mosnier, Jean-Francois Laboisse, Christian Vergnolle, Nathalie Andreoletti, Olivier Roth, Marie-Paule Liblau, Roland Fournié, Gilbert J. Saoudi, Abdelhadi Dejean, Anne S. PLoS Genet Research Article Spontaneous or chemically induced germline mutations, which lead to Mendelian phenotypes, are powerful tools to discover new genes and their functions. Here, we report an autosomal recessive mutation that occurred spontaneously in a Brown-Norway (BN) rat colony and was identified as causing marked T cell lymphopenia. This mutation was stabilized in a new rat strain, named BN(m) for “BN mutated.” In BN(m) rats, we found that the T cell lymphopenia originated in the thymus, was intrinsic to CD4 T lymphocytes, and was associated with the development of an inflammatory bowel disease. Furthermore, we demonstrate that the suppressive activity of both peripheral and thymic CD4(+) CD25(bright) regulatory T cells (Treg) is defective in BN(m) rats. Complementation of mutant animals with BN Treg decreases disease incidence and severity, thus suggesting that the impaired Treg function is involved in the development of inflammatory bowel disease in BN(m) rats. Moreover, the cytokine profile of effector CD4 T cells is skewed toward Th2 and Th17 phenotypes in BN(m) rats. Linkage analysis and genetic dissection of the CD4 T cell lymphopenia in rats issued from BN(m)×DA crosses allowed the localization of the mutation on chromosome 1, within a 1.5 megabase interval. Gene expression and sequencing studies identified a frameshift mutation caused by a four-nucleotide insertion in the Themis gene, leading to its disruption. This result is the first to link Themis to the suppressive function of Treg and to suggest that, in Themis-deficient animals, defect of this function is involved in intestinal inflammation. Thus, this study highlights the importance of Themis as a new target gene that could participate in the pathogenesis of immune diseases characterized by chronic inflammation resulting from a defect in the Treg compartment. Public Library of Science 2012-01-19 /pmc/articles/PMC3261907/ /pubmed/22275874 http://dx.doi.org/10.1371/journal.pgen.1002461 Text en Chabod 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 Chabod, Marianne Pedros, Christophe Lamouroux, Lucille Colacios, Céline Bernard, Isabelle Lagrange, Dominique Balz-Hara, Daniela Mosnier, Jean-Francois Laboisse, Christian Vergnolle, Nathalie Andreoletti, Olivier Roth, Marie-Paule Liblau, Roland Fournié, Gilbert J. Saoudi, Abdelhadi Dejean, Anne S. A Spontaneous Mutation of the Rat Themis Gene Leads to Impaired Function of Regulatory T Cells Linked to Inflammatory Bowel Disease |
title | A Spontaneous Mutation of the Rat Themis Gene Leads to Impaired Function of Regulatory T Cells Linked to Inflammatory Bowel Disease |
title_full | A Spontaneous Mutation of the Rat Themis Gene Leads to Impaired Function of Regulatory T Cells Linked to Inflammatory Bowel Disease |
title_fullStr | A Spontaneous Mutation of the Rat Themis Gene Leads to Impaired Function of Regulatory T Cells Linked to Inflammatory Bowel Disease |
title_full_unstemmed | A Spontaneous Mutation of the Rat Themis Gene Leads to Impaired Function of Regulatory T Cells Linked to Inflammatory Bowel Disease |
title_short | A Spontaneous Mutation of the Rat Themis Gene Leads to Impaired Function of Regulatory T Cells Linked to Inflammatory Bowel Disease |
title_sort | spontaneous mutation of the rat themis gene leads to impaired function of regulatory t cells linked to inflammatory bowel disease |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3261907/ https://www.ncbi.nlm.nih.gov/pubmed/22275874 http://dx.doi.org/10.1371/journal.pgen.1002461 |
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