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

Tiing Jen Loh, Jia Jia Lim, Claerwen M. Jones, Hien Thy Dao, Mai T. Tran, Daniel G. Baker, Nicole L. Gruta, Hugh H. Reid () and Jamie Rossjohn ()
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Tiing Jen Loh: Monash University
Jia Jia Lim: Monash University
Claerwen M. Jones: Monash University
Hien Thy Dao: Monash University
Mai T. Tran: Monash University
Daniel G. Baker: Horsham
Nicole L. Gruta: Monash University
Hugh H. Reid: Monash University
Jamie Rossjohn: Monash University

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-50511-w

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