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

• Published in: The Journal of immunology (1950) 2011-02, Vol.186 (4), p.2672-2680
• Main Authors: Bowness, Paul, Ridley, Anna, Shaw, Jacqueline, Chan, Antoni T, Wong-Baeza, Isabel, Fleming, Myles, Cummings, Fraser, McMichael, Andrew, Kollnberger, Simon
• Format: Article
• Language: English
• Subjects: Antigen-Presenting Cells - immunology; Antigen-Presenting Cells - metabolism; CD4 Lymphocyte Count; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; Cell Line; Cell Proliferation; Cell Survival - immunology; Coculture Techniques; Female; HLA-B27 Antigen - biosynthesis; HLA-B27 Antigen - chemistry; HLA-B27 Antigen - physiology; Humans; Interleukin-17 - biosynthesis; Lymphocyte Activation - immunology; Male; Protein Multimerization - immunology; Receptors, Interleukin - biosynthesis; Receptors, Interleukin - blood; Receptors, KIR3DL2 - biosynthesis; Spondylitis, Ankylosing - immunology; Spondylitis, Ankylosing - metabolism; Spondylitis, Ankylosing - pathology; Superantigens - pharmacology; Th17 Cells - immunology; Th17 Cells - metabolism; Th17 Cells - pathology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1002653

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 B27(2)), which, unlike classical HLA-B27, bind the killer-cell Ig-like receptor KIR3DL2. In this article, we show that B27(2)-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.