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T cells specific for post-translational modifications escape intrathymic tolerance induction

Establishing effective central tolerance requires the promiscuous expression of tissue-restricted antigens by medullary thymic epithelial cells. However, whether central tolerance also extends to post-translationally modified proteins is not clear. Here we show a mouse model of autoimmunity in which...

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Autores principales: Raposo, Bruno, Merky, Patrick, Lundqvist, Christina, Yamada, Hisakata, Urbonaviciute, Vilma, Niaudet, Colin, Viljanen, Johan, Kihlberg, Jan, Kyewski, Bruno, Ekwall, Olov, Holmdahl, Rikard, Bäcklund, Johan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5783942/
https://www.ncbi.nlm.nih.gov/pubmed/29367624
http://dx.doi.org/10.1038/s41467-017-02763-y
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author Raposo, Bruno
Merky, Patrick
Lundqvist, Christina
Yamada, Hisakata
Urbonaviciute, Vilma
Niaudet, Colin
Viljanen, Johan
Kihlberg, Jan
Kyewski, Bruno
Ekwall, Olov
Holmdahl, Rikard
Bäcklund, Johan
author_facet Raposo, Bruno
Merky, Patrick
Lundqvist, Christina
Yamada, Hisakata
Urbonaviciute, Vilma
Niaudet, Colin
Viljanen, Johan
Kihlberg, Jan
Kyewski, Bruno
Ekwall, Olov
Holmdahl, Rikard
Bäcklund, Johan
author_sort Raposo, Bruno
collection PubMed
description Establishing effective central tolerance requires the promiscuous expression of tissue-restricted antigens by medullary thymic epithelial cells. However, whether central tolerance also extends to post-translationally modified proteins is not clear. Here we show a mouse model of autoimmunity in which disease development is dependent on post-translational modification (PTM) of the tissue-restricted self-antigen collagen type II. T cells specific for the non-modified antigen undergo efficient central tolerance. By contrast, PTM-reactive T cells escape thymic selection, though the PTM variant constitutes the dominant form in the periphery. This finding implies that the PTM protein is absent in the thymus, or present at concentrations insufficient to induce negative selection of developing thymocytes and explains the lower level of tolerance induction against the PTM antigen. As the majority of self-antigens are post-translationally modified, these data raise the possibility that T cells specific for other self-antigens naturally subjected to PTM may escape central tolerance induction by a similar mechanism.
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spelling pubmed-57839422018-01-26 T cells specific for post-translational modifications escape intrathymic tolerance induction Raposo, Bruno Merky, Patrick Lundqvist, Christina Yamada, Hisakata Urbonaviciute, Vilma Niaudet, Colin Viljanen, Johan Kihlberg, Jan Kyewski, Bruno Ekwall, Olov Holmdahl, Rikard Bäcklund, Johan Nat Commun Article Establishing effective central tolerance requires the promiscuous expression of tissue-restricted antigens by medullary thymic epithelial cells. However, whether central tolerance also extends to post-translationally modified proteins is not clear. Here we show a mouse model of autoimmunity in which disease development is dependent on post-translational modification (PTM) of the tissue-restricted self-antigen collagen type II. T cells specific for the non-modified antigen undergo efficient central tolerance. By contrast, PTM-reactive T cells escape thymic selection, though the PTM variant constitutes the dominant form in the periphery. This finding implies that the PTM protein is absent in the thymus, or present at concentrations insufficient to induce negative selection of developing thymocytes and explains the lower level of tolerance induction against the PTM antigen. As the majority of self-antigens are post-translationally modified, these data raise the possibility that T cells specific for other self-antigens naturally subjected to PTM may escape central tolerance induction by a similar mechanism. Nature Publishing Group UK 2018-01-24 /pmc/articles/PMC5783942/ /pubmed/29367624 http://dx.doi.org/10.1038/s41467-017-02763-y Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Raposo, Bruno
Merky, Patrick
Lundqvist, Christina
Yamada, Hisakata
Urbonaviciute, Vilma
Niaudet, Colin
Viljanen, Johan
Kihlberg, Jan
Kyewski, Bruno
Ekwall, Olov
Holmdahl, Rikard
Bäcklund, Johan
T cells specific for post-translational modifications escape intrathymic tolerance induction
title T cells specific for post-translational modifications escape intrathymic tolerance induction
title_full T cells specific for post-translational modifications escape intrathymic tolerance induction
title_fullStr T cells specific for post-translational modifications escape intrathymic tolerance induction
title_full_unstemmed T cells specific for post-translational modifications escape intrathymic tolerance induction
title_short T cells specific for post-translational modifications escape intrathymic tolerance induction
title_sort t cells specific for post-translational modifications escape intrathymic tolerance induction
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5783942/
https://www.ncbi.nlm.nih.gov/pubmed/29367624
http://dx.doi.org/10.1038/s41467-017-02763-y
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