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

Bruno Raposo, Patrick Merky, Christina Lundqvist, Hisakata Yamada, Vilma Urbonaviciute, Colin Niaudet, Johan Viljanen, Jan Kihlberg, Bruno Kyewski, Olov Ekwall, Rikard Holmdahl () and Johan Bäcklund
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Bruno Raposo: Karolinska Institutet
Patrick Merky: Karolinska Institutet
Christina Lundqvist: University of Gothenburg
Hisakata Yamada: Kyushu University
Vilma Urbonaviciute: Karolinska Institutet
Colin Niaudet: Karolinska Institutet
Johan Viljanen: BMC Uppsala University
Jan Kihlberg: BMC Uppsala University
Bruno Kyewski: German Cancer Research Center (DKFZ)
Olov Ekwall: University of Gothenburg
Rikard Holmdahl: Karolinska Institutet
Johan Bäcklund: Karolinska Institutet

Nature Communications, 2018, vol. 9, issue 1, 1-11

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-017-02763-y

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