Activation-Induced Killer Cell Immunoglobulin-like Receptor 3DL2 Binding to HLA-B27 Licenses Pathogenic T Cell Differentiation in Spondyloarthritis.
Activation-Induced Killer Cell Immunoglobulin-like Receptor 3DL2 Binding to HLA-B27 Licenses Pathogenic T Cell Differentiation in Spondyloarthritis.
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DOI：
10.1002/art.39515
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发表时间：
2016-04
期刊：
影响因子：
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通讯作者：
Kollnberger S
中科院分区：
文献类型：
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作者：
Ridley A;Hatano H;Wong-Baeza I;Shaw J;Matthews KK;Al-Mossawi H;Ladell K;Price DA;Bowness P;Kollnberger S
在脊椎关节炎（SpA）中，CD4+ T细胞表达杀伤细胞免疫球蛋白样受体3DL2 （KIR - 3DL2）的数量增加。本研究的目的是确定诱导KIR‐3DL2表达的因素，并表征HLA-B27与SpA中表达KIR‐3DL2的CD4+ T细胞表型和功能之间的关系。研究共纳入34例B27+ SpA患者、28例年龄和性别匹配的健康对照（20例B27 -和8例B27+）和9例类风湿关节炎患者。采用流式细胞术、定量聚合酶链反应、Western blotting等方法研究外周血和滑膜液CD4+ T细胞KIR-3DL2的表达及其他表型特征。通过模板开关锚定逆转录聚合酶链反应和测序分析确定T细胞受体的克隆性。细胞因子用酶联免疫吸附法测定。细胞激活诱导初始和效应CD4+ T细胞表达KIR‐3DL2。KIR‐3DL2结合B27+细胞可促进KIR‐3DL2、Th17特异性转录因子视黄酸受体相关孤儿核受体γ - t和抗凋亡因子B细胞淋巴瘤2的表达。强直性脊柱炎患者的KIR‐3DL2+CD4+ T细胞是寡克隆的，并且富含T细胞活化标记物和肠道归巢受体CCR9。当B27+抗原呈递细胞存在时，KIR - 3DL2+CD4+ T细胞产生较少的白细胞介素- 2 (IL - 2)，但产生较多的IL - 17。这种作用被HC10阻断，HC10是一种抑制KIR‐3DL2与B27重链结合的抗体。KIR‐3DL2结合HLA-B27促进SpA中Th17细胞分化。这些发现提高了靶向HLA-B27-KIR - 3DL2相互作用治疗B27+ SpA患者的治疗潜力。
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. 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. 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. 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.