HLA-B27-restricted CD8 T cells derived from synovial fluids of patients with reactive arthritis and ankylosing spondylitis

Abstract

Ankylosing spondylitis and seronegative spondylarthropathies such as Reiter's syndrome and reactive arthritis are strongly associated with HLA-B27. However, the mechanisms by which HLA-B27 is involved in disease susceptibility and pathogenesis are unknown. If the disease association is a consequence of HLA-B27's physiological function in antigen presentation, the disease should be mediated by cytotoxic T lymphocytes (CTLs) that recognise bacterial or self peptides presented by HLA-B27. Proof of this arthritogenic peptide model requires isolation of B27-restricted CD8 T cells from arthritic joints of patients with spondylarthropathies. An important question is whether "arthritogenic" bacteria such as yersinia or salmonella can generate HLA-B27-restricted bacteria-specific CTLs. We describe such HLA-B27-restricted CTLs. We tested a panel of 354 alpha beta-TCR CD8 T lymphocyte clones (TLCs) that had been derived from the synovial fluid of 4 patients with reactive arthritis and 2 patients with ankylosing spondylitis. In 1 patient with yersinia-induced arthritis, 2 TLCs were identified that killed specifically yersinia-infected B27 target cells. In another patient with salmonella-induced arthritis, 1 B27-restricted CD8 TLC that recognised both salmonella and yersinia was identified. In 5 of the 6 patients autoreactive CTLs were found, 5 of which showed B27-restricted killing of uninfected cell lines. B27-restricted CTLs with specificity for arthritogenic bacteria or autoantigens provide a missing link in the pathogenesis of the HLA-B27-associated spondylarthropathies.