Autoimmunity-associated T cell receptors recognize HLA-B*27-bound peptides

Human leucocyte antigen B*27 (HLA-B*27) is strongly associated with inflammatory diseases of the spine and pelvis (for example, ankylosing spondylitis (AS)) and the eye (that is, acute anterior uveitis (AAU))(1). How HLA-B*27 facilitates disease remains unknown, but one possible mechanism could involve presentation of pathogenic peptides to CD8(+) T cells. Here we isolated orphan T cell receptors (TCRs) expressing a disease-associated public beta-chain variable region-complementary-determining region 3 beta (BV9-CDR3 beta) motif(2-4) from blood and synovial fluid T cells from individuals with AS and from the eye in individuals with AAU. These TCRs showed consistent alpha-chain variable region (AV21) chain pairing and were clonally expanded in the joint and eye. We used HLA-B*27:05 yeast display peptide libraries to identify shared self-peptides and microbial peptides that activated the AS- and AAU-derived TCRs. Structural analysis revealed that TCR cross-reactivity for peptide-MHC was rooted in a shared binding motif present in both self-antigens and microbial antigens that engages the BV9-CDR3 beta TCRs. These findings support the hypothesis that microbial antigens and self-antigens could play a pathogenic role in HLA-B*27-associated disease.