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

Journal article
Authors Bruno Raposo
Patrick Merky
Christina Lundqvist
Hisakata Yamada
Vilma Urbonaviciute
Colin Niaudet
Johan Viljanen
Jan Kihlberg
Bruno Kyewski
Olov Ekwall
Rikard Holmdahl
Johan Bäcklund
Published in Nature communications
Volume 9
Issue 1
Pages 353
ISSN 2041-1723
Publication year 2018
Published at Institute of Medicine, Department of Rheumatology and Inflammation Research
Institute of Clinical Sciences, Department of Pediatrics
Pages 353
Language en
Links dx.doi.org/10.1038/s41467-017-02763...
www.ncbi.nlm.nih.gov/entrez/query.f...
Subject categories Immunology in the medical area

Abstract

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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