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T cells specific for post-translational modifications escape intrathymic tolerance induction
Karolinska Inst, Sect Med Inflammat Res, Dept Med Biochem & Biophys, Scheeles Vag 2, S-17177 Stockholm, Sweden.;Harvard Med Sch, Dept Microbiol & Immunobiol, 77 Ave Louis Pasteur,NRB 836, Boston, MA 02115 USA..
Karolinska Inst, Sect Med Inflammat Res, Dept Med Biochem & Biophys, Scheeles Vag 2, S-17177 Stockholm, Sweden..
Univ Gothenburg, Sahlgrenska Acad, Inst Med, Dept Rheumatol & Inflammat Res, S-41346 Gothenburg, Sweden..
Kyushu Univ, Med Inst Bioregulat, Div Host Def, Fukuoka 8128582, Japan..
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2018 (English)In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 9, article id 353Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP , 2018. Vol. 9, article id 353
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Medical and Health Sciences
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URN: urn:nbn:se:uu:diva-343795DOI: 10.1038/s41467-017-02763-yISI: 000423155700011PubMedID: 29367624OAI: oai:DiVA.org:uu-343795DiVA, id: diva2:1188251
Funder
Swedish Foundation for Strategic Research Knut and Alice Wallenberg FoundationSwedish Research CouncilAvailable from: 2018-03-07 Created: 2018-03-07 Last updated: 2018-03-07Bibliographically approved

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