The Shared Susceptibility Epitope Of Hla-Dr4 Binds Citrullinated Self-Antigens And The Tcr

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 Fib beta-74cit(69-81) peptide led to a population of HLA-DR4(Fib beta-74cit69-81) tetramer(+) T cells that exhibited biased T cell receptor (TCR) beta 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 (Fib beta-72,74cit(69-81)) 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 beta chain usage toward the Fib.-74cit(69-81) peptide was observed in healthy HLA-DR4(+) individuals and patients with HLA-DR4(+) RA, thereby suggesting a link to human RA.