title: Activation-Induced Killer Cell Immunoglobulin-like Receptor 3DL2 Binding to HLA-B27 Licenses Pathogenic T Cell Differentiation in Spondyloarthritis.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors: Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Oxford University, Oxford, UK.
authors: Anna
authors: A
authors: Ridley
authors: Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Oxford University, Oxford, UK.
authors: Hiroko
authors: H
authors: Hatano
authors: Isabel Wong-Baeza, PhD: Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Oxford University, Oxford, UK, and National School of Biological Sciences, National Polytechnic Institute, Mexico City, Mexico.
authors: Isabel
authors: I
authors: Wong-Baeza
authors: Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Oxford University, Oxford, UK.
authors: Jacqueline
authors: J
authors: Shaw
authors: QIMR, Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
authors: Katherine K
authors: KK
authors: Matthews
authors: Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Oxford University, Oxford, UK.
authors: Hussein
authors: H
authors: Al-Mossawi
authors: Cardiff University School of Medicine, Cardiff, UK.
authors: Kristin
authors: K
authors: Ladell
authors: Cardiff University School of Medicine, Cardiff, UK, and National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland.
authors: David A
authors: DA
authors: Price
authors: Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Oxford University, Oxford, UK.
authors: Paul
authors: P
authors: Bowness
authors: Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology, and Musculoskeletal Sciences, Oxford University, Oxford, UK, and Cardiff University School of Medicine, Cardiff, UK.
authors: Simon
authors: S
authors: Kollnberger
mesh_terms: D000328:Adult; D000368:Aged; D015535:Arthritis, Psoriatic / Q000276:immunology; D016918:Arthritis, Reactive / Q000276:immunology; D001172:Arthritis, Rheumatoid / Q000276:immunology; D015153:Blotting, Western; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D016022:Case-Control Studies; D002454:Cell Differentiation / Q000276:immunology*; D016207:Cytokines / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D015796:HLA-B27 Antigen / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D011948:Receptors, Antigen, T-Cell / Q000235:genetics; D054347:Receptors, KIR3DL2 / Q000276:immunology* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D025242:Spondylarthropathies / Q000276:immunology*; D013167:Spondylitis, Ankylosing / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D058504:Th17 Cells / Q000276:immunology*; D059467:Transcriptome; D055815:Young Adult
chemical_list: D016207:Cytokines; D015796:HLA-B27 Antigen; C515084:KIR3DL2 protein, human; D011948:Receptors, Antigen, T-Cell; D054347:Receptors, KIR3DL2