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

• Published in: Nature communications Vol. 15; no. 1; pp. 6201 - 17
• Main Authors: 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., Rossjohn, Jamie
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 23.07.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 631/250/1619/554/1898; 631/250/2152; 631/250/2152/1566/2493; 631/250/38; 631/535/1266; 82/103; 82/83; Animals; Antigenic determinants; Arthritis; Arthritis, Rheumatoid - genetics; Arthritis, Rheumatoid - immunology; CD4 antigen; CD4-Positive T-Lymphocytes - immunology; Citrullination; Citrulline; Citrulline - immunology; Citrulline - metabolism; Crystallography, X-Ray; Drb1 protein; Epitopes; Epitopes - immunology; Epitopes, T-Lymphocyte - immunology; Fibrinogen; Histocompatibility antigen HLA; HLA-DR4 Antigen - genetics; HLA-DR4 Antigen - immunology; Humanities and Social Sciences; Humans; Lymphocytes; Lymphocytes T; Mice; Mice, Transgenic; multidisciplinary; Peptides; Phosphopyruvate hydratase; Phosphopyruvate Hydratase - genetics; Phosphopyruvate Hydratase - immunology; Phosphopyruvate Hydratase - metabolism; Receptors; Receptors, Antigen, T-Cell - immunology; Receptors, Antigen, T-Cell - metabolism; Receptors, Antigen, T-Cell, alpha-beta - genetics; Receptors, Antigen, T-Cell, alpha-beta - immunology; Receptors, Antigen, T-Cell, alpha-beta - metabolism; Rheumatoid arthritis; Science; Science (multidisciplinary); T cell receptors; Transgenic animals; Transgenic mice; Vimentin; Vimentin - genetics; Vimentin - immunology; Vimentin - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-50511-w

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-64cit 59-71 and α-enolase-15cit 10-22 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−74cit 69-81 epitope. Moreover, shared TRAV26-1 gene usage is evident in four α-enolase-15cit 10-22 reactive T cells in three human samples. Crystal structures of mouse TRAV6 + and human TRAV26-1 + TCR-HLA-DR4 complexes presenting vimentin-64cit 59-71 and α-enolase-15cit 10-22 , 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. CD4 + T cells recognising shared susceptibility epitope (SE) encoded HLA-DRB1 presenting citrullinated self-peptides are implicated in rheumatoid arthritis. Here the authors characterise the T cell receptor repertoire and structure during recognition of different citrullinated self-epitopes in HLA-DR4 transgenic mice and ACPA + RA patients.