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.


Individuals expressing HLA-DR4 bearing the shared susceptibility epitope (SE) have an increased risk of developing rheumatoid arthritis (RA). Posttranslational modification of self-proteins via citrullination leads to the formation of neoantigens that can be presented by HLA-DR4 SE allomorphs. However, in T cell–mediated autoimmunity, the interplay between the HLA molecule, posttranslationally modified epitope(s), and the responding T cell repertoire remains unclear. In HLA-DR4 transgenic mice, we show that immunization with a Fibβ-74cit69-81 peptide led to a population of HLA-DR4Fibβ-74cit69-81 tetramer+ T cells that exhibited biased T cell receptor (TCR) β chain usage, which was attributable to selective clonal expansion from the preimmune repertoire. Crystal structures of pre- and postimmune TCRs showed that the SE of HLA-DR4 represented a main TCR contact zone. Immunization with a double citrullinated epitope (Fibβ-72,74cit69-81) altered the responding HLA-DR4 tetramer+ T cell repertoire, which was due to the P2-citrulline residue interacting with the TCR itself. We show that the SE of HLA-DR4 has dual functionality, namely, presentation and a direct TCR recognition determinant. Analogous biased TCR β chain usage toward the Fibβ-74cit69-81 peptide was observed in healthy HLA-DR4+ individuals and patients with HLA-DR4+ RA, thereby suggesting a link to human RA.

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