TY  - JOUR
AU  - Raposo, Bruno
AU  - Merky, Patrick
AU  - Lundqvist, Christina
AU  - Yamada, Hisakata
AU  - Urbonaviciute, Vilma
AU  - Niaudet, Colin
AU  - Viljanen, Johan
AU  - Kihlberg, Jan
AU  - Kyewski, Bruno
AU  - Ekwall, Olov
AU  - Holmdahl, Rikard
AU  - Bäcklund, Johan
TI  - T cells specific for post-translational modifications escape intrathymic tolerance induction.
JO  - Nature Communications
VL  - 9
IS  - 1
SN  - 2041-1723
CY  - [London]
PB  - Nature Publishing Group UK
M1  - DKFZ-2019-00461
SP  - 353
PY  - 2018
AB  - 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.
KW  - Autoantigens (NLM Chemicals)
KW  - Collagen Type II (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:29367624
C2  - pmc:PMC5783942
DO  - DOI:10.1038/s41467-017-02763-y
UR  - https://inrepo02.dkfz.de/record/142744
ER  -