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

Author

Listed:
  • 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
    Cardiff University School of Medicine)

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.

Suggested Citation

  • Tiing Jen Loh & Jia Jia Lim & Claerwen M. Jones & Hien Thy Dao & Mai T. Tran & Daniel G. Baker & Nicole L. Gruta & Hugh H. Reid & Jamie Rossjohn, 2024. "The molecular basis underlying T cell specificity towards citrullinated epitopes presented by HLA-DR4," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-50511-w
    DOI: 10.1038/s41467-024-50511-w
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    1. Mai T. Tran & Pouya Faridi & Jia Jia Lim & Yi Tian Ting & Goodluck Onwukwe & Pushpak Bhattacharjee & Claerwen M. Jones & Eleonora Tresoldi & Fergus J. Cameron & Nicole L. Gruta & Anthony W. Purcell & , 2021. "T cell receptor recognition of hybrid insulin peptides bound to HLA-DQ8," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
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