OBJECTIVE: In the spondyloarthritides (SpA), increased numbers of CD4+ T cells express killer cell immunoglobulin-like receptor 3DL2 (KIR-3DL2). The aim of this study was to determine the factors that induce KIR-3DL2 expression, and to characterize the relationship between HLA-B27 and the phenotype and function of KIR-3DL2-expressing CD4+ T cells in SpA. METHODS: In total, 34 B27+ patients with SpA, 28 age- and sex-matched healthy controls (20 B27- and 8 B27+), and 9 patients with rheumatoid arthritis were studied. KIR-3DL2 expression and other phenotypic characteristics of peripheral blood and synovial fluid CD4+ T cells were studied by flow cytometry, quantitative polymerase chain reaction, and Western blotting. T cell receptor clonality was determined by template-switch anchored reverse transcription-polymerase chain reaction and sequencing analysis. Cytokines were measured by enzyme-linked immunosorbent assay. RESULTS: Cellular activation induced KIR-3DL2 expression on both naive and effector CD4+ T cells. KIR-3DL2 binding to B27+ cells promoted expression of KIR-3DL2, the Th17-specific transcription factor retinoic acid receptor-related orphan nuclear receptor γt, and the antiapoptotic factor B cell lymphoma 2. KIR-3DL2+CD4+ T cells in patients with ankylosing spondylitis were oligoclonal and enriched for markers of T cell activation and for the gut homing receptor CCR9. In the presence of B27+ antigen-presenting cells, KIR-3DL2+CD4+ T cells produced less interleukin-2 (IL-2) but more IL-17. This effect was blocked by HC10, an antibody that inhibits the binding of KIR-3DL2 to B27 heavy chains. CONCLUSION: KIR-3DL2 binding to HLA-B27 licenses Th17 cell differentiation in SpA. These findings raise the therapeutic potential of targeting HLA-B27-KIR-3DL2 interactions for the treatment of B27+ patients with SpA.

Original publication

DOI

10.1002/art.39515

Type

Journal article

Journal

Arthritis Rheumatol

Publication Date

04/2016

Volume

68

Pages

901 - 914

Keywords

Adult, Aged, Arthritis, Psoriatic, Arthritis, Reactive, Arthritis, Rheumatoid, Blotting, Western, CD4-Positive T-Lymphocytes, Case-Control Studies, Cell Differentiation, Cytokines, Enzyme-Linked Immunosorbent Assay, Female, Flow Cytometry, HLA-B27 Antigen, Humans, Male, Middle Aged, Receptors, Antigen, T-Cell, Receptors, KIR3DL2, Reverse Transcriptase Polymerase Chain Reaction, Spondylarthropathies, Spondylitis, Ankylosing, T-Lymphocytes, Th17 Cells, Transcriptome, Young Adult