Premature Cell Senescence and T Cell Receptor-Independent Activation of CD8+T Cells in Juvenile Idiopathic Arthritis
Premature Cell Senescence and T Cell Receptor-Independent Activation of CD8+T Cells in Juvenile Idiopathic Arthritis
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DOI：
10.1002/art.38015
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发表时间：
2013-08-01
影响因子：
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通讯作者：
Vallejo, Abbe N.
中科院分区：
文献类型：
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作者：
Dvergsten, Jeffrey A.;Mueller, Robert G.;Vallejo, Abbe N.
目标。缺乏CD28的CD8+T细胞最初被报道为幼年特发性关节炎(JIA)的特征，但这些不寻常的细胞与该疾病的相关性仍有待阐明。由于最近有证据表明CD28细胞丢失是终末分化淋巴细胞的典型特征，本研究的目的是检测JIA患者CD8+T细胞的功能亚群。采集98例确诊为JIA的患儿的血液和(或)关节液样本。同时采集33例健康献血者外周血和13例脐带血标本。筛选CD8+和CD4+T细胞寻找新的受体，并在有需要的情况下进行生物检测，以确定所识别的受体的功能相关性。JIA患者有一个端粒缩短的幼稚T细胞室，他们的整个T细胞库的增殖能力都降低了。CD31+CD28(空)CD8+T细胞过多，这是少关节型JIA(n=62)较多关节型JIA(n=36)的显著特征。CD31+CD28(空)CD8+T细胞有丝分裂能力有限，高水平表达衰老抗原组蛋白-γ、H_2AX和/或p16。CD31不依赖于T细胞受体(TCR)，可充分诱导酪氨酸磷酸化、囊泡胞吐、干扰素-γ和白介素10的产生。这些数据首次提供了JIA病理生理学中以CD31+CD28(空)CD8+T细胞为代表的细胞衰老的证据。这些不寻常的细胞以TCR非依赖的方式激活，表明它们是不适应的，可能成为免疫治疗的潜在靶点。
Objective. CD8+ T cells lacking CD28 were originally reported to be a characteristic feature of juvenile idiopathic arthritis (JIA), but the relevance of these unusual cells to this disease remains to be elucidated. Because of recent evidence that loss of CD28 cells is typical of terminally differentiated lymphocytes, the aim of this study was to examine functional subsets of CD8+ T cells in patients with JIA.Methods. Blood and/or waste synovial fluid samples were collected from children with a definite diagnosis of JIA (n = 98). Deidentified peripheral blood (n = 33) and cord blood (n = 13) samples from healthy donors were also collected. CD8+ and CD4+ T cells were screened for novel receptors, and where indicated, bioassays were performed to determine the functional relevance of the identified receptor.Results. JIA patients had a naive T cell compartment with shortened telomeres, and their entire T cell pool had reduced proliferative capacity. They had an overabundance of CD31+CD28(null)CD8+ T cells, which was a significant feature of oligoarticular JIA (n = 62) as compared to polyarticular JIA (n = 36). CD31+ CD28(null)CD8+ T cells had limited mitotic capacity and expressed high levels of the senescence antigens histone gamma H2AX and/or p16. Ligation of CD31, which was independent of the T cell receptor (TCR), sufficiently induced tyrosine phosphorylation, vesicle exocytosis, and production of interferon-gamma and interleukin-10.Conclusion. These data provide the first evidence of cell senescence, as represented by CD31 + CD28(null)CD8+ T cells, in the pathophysiology of JIA. Activation of these unusual cells in a TCR-independent manner suggests that they are maladaptive and could be potential targets for immunotherapy.