The molecular basis underlying T cell specificity towards citrullinated epitopes presented by HLA-DR4

Loh, Tiing Jen, Lim, Jia Jia, Jones, Claerwen M., Dao, Hien Thy, Tran, Mai T., Baker, Daniel G., La Gruta, Nicole L., Reid, Hugh H. and Rossjohn, Jamie ORCID: https://orcid.org/0000-0002-2020-7522 2024. The molecular basis underlying T cell specificity towards citrullinated epitopes presented by HLA-DR4. Nature Communications 15 (1) , 6201. 10.1038/s41467-024-50511-w

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Abstract

CD4+ T cells recognising citrullinated self-epitopes presented by HLA-DRB1 bearing the shared susceptibility epitope (SE) are implicated in rheumatoid arthritis (RA). However, the underlying T cell receptor (TCR) determinants of epitope specificity towards distinct citrullinated peptide antigens, including vimentin-64cit59-71 and α-enolase-15cit10-22 remain unclear. Using HLA-DR4-tetramers, we examine the T cell repertoire in HLA-DR4 transgenic mice and observe biased TRAV6 TCR gene usage across these two citrullinated epitopes which matches with TCR bias previously observed towards the fibrinogen β−74cit69-81 epitope. Moreover, shared TRAV26-1 gene usage is evident in four α-enolase-15cit10-22 reactive T cells in three human samples. Crystal structures of mouse TRAV6+ and human TRAV26-1+ TCR-HLA-DR4 complexes presenting vimentin-64cit59-71 and α-enolase-15cit10-22, respectively, show three-way interactions between the TCR, SE, citrulline, and the basis for the biased selection of TRAV genes. Position 2 of the citrullinated epitope is a key determinant underpinning TCR specificity. Accordingly, we provide a molecular basis of TCR specificity towards citrullinated epitopes.

Item Type:	Article
Date Type:	Published Online
Status:	Published
Schools:	Medicine
Additional Information:	License information from Publisher: LICENSE 1: URL: http://creativecommons.org/licenses/by/4.0/, Type: open-access
Publisher:	Nature Research
ISSN:	2041-1723
Date of First Compliant Deposit:	25 July 2024
Date of Acceptance:	12 July 2024
Last Modified:	25 Jul 2024 08:30
URI:	https://orca.cardiff.ac.uk/id/eprint/170910

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