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 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.
Medical Research Council Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Headington, Oxford OX3 9DS, United Kingdom.
Paul
P
Bowness
Anna
A
Ridley
Jacqueline
J
Shaw
Antoni T
AT
Chan
Isabel
I
Wong-Baeza
Myles
M
Fleming
Fraser
F
Cummings
Andrew
A
McMichael
Simon
S
Kollnberger
D000938:Antigen-Presenting Cells / Q000276:immunology / Q000378:metabolism; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation; D002470:Cell Survival / Q000276:immunology; D018920:Coculture Techniques; D005260:Female; D015796:HLA-B27 Antigen / Q000096:biosynthesis / Q000737:chemistry / Q000502:physiology*; D006801:Humans; D020381:Interleukin-17 / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D055503:Protein Multimerization / Q000276:immunology*; D018123:Receptors, Interleukin / Q000096:biosynthesis / Q000097:blood; D054347:Receptors, KIR3DL2 / Q000096:biosynthesis*; D013167:Spondylitis, Ankylosing / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D018089:Superantigens / Q000494:pharmacology; D058504:Th17 Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*
D015796:HLA-B27 Antigen; C515500:IL23R protein, human; D020381:Interleukin-17; C515084:KIR3DL2 protein, human; D018123:Receptors, Interleukin; D054347:Receptors, KIR3DL2; D018089:Superantigens
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