Th17 cells expressing KIR3DL2⁺ and responsive to HLA-B27 homodimers are increased in ankylosing spondylitis

CD4 Th cells producing the proinflammatory cytokine IL-17 (Th17) have been implicated in a number of inflammatory arthritides including the spondyloarthritides. Th17 development is promoted by IL-23. Ankylosing spondylitis, the most common spondyloarthritis (SpA), is genetically associated with both HLA-B27 (B27) and IL-23R polymorphisms; however, the link remains unexplained. We have previously shown that B27 can form H chain dimers (termed B27₂), which, unlike classical HLA-B27, bind the killer-cell Ig-like receptor KIR3DL2. In this article, we show that B27₂-expressing APCs stimulate the survival, proliferation, and IL-17 production of KIR3DL2 ⁺ CD4 T cells. KIR3DL2⁺ CD4 T cells are expanded and enriched for IL-17 production in the blood and synovial fluid of patients with SpA. Despite KIR3DL2⁺ cells comprising a mean of just 15% of CD4 T in the peripheral blood of SpA patients, this subset accounted for 70% of the observed increase in Th17 numbers in SpA patients compared with control subjects. TCR-stimulated peripheral blood KIR3DL2⁺ CD4 T cell lines from SpA patients secreted 4-fold more IL-17 than KIR3DL2⁺ lines from controls or KIR3DL2^- CD4 T cells. Strikingly, KIR3DL2⁺ CD4 T cells account for the majority of peripheral blood CD4 T cell IL-23R expression and produce more IL-17 in the presence of IL-23. Our findings link HLA-B27 with IL-17 production and suggest new therapeutic strategies in ankylosing spondylitis/SpA.