Research ArticleAUTOIMMUNITY

The shared susceptibility epitope of HLA-DR4 binds citrullinated self-antigens and the TCR

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Science Immunology  16 Apr 2021:
Vol. 6, Issue 58, eabe0896
DOI: 10.1126/sciimmunol.abe0896

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TCR detection of citrullinated epitopes

The autoreactive T cell repertoire driving disease activity in rheumatoid arthritis (RA) includes CD4+ T cells that recognize MHC-bound peptides with arginine residues posttranslationally modified to citrulline. Some HLA-DRB1 alleles have a shared susceptibility epitope associated with increased RA incidence. Lim et al. analyzed the repertoire, binding properties, and structure of multiple T cell receptors (TCRs) derived from humanized mice reactive with citrullinated peptides presented by HLA-DR4. TCR repertoire analysis revealed a citrullinated antigen-specific motif, conserved in both mice and humans. Crystal structures revealed direct contact of the TCR with the shared epitope on HLA-DR4. Alleles of HLA-DRB1 with the shared epitope contribute to the development of RA through both binding of stimulatory peptide epitopes and direct contact with a biased set of TCRs.

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