University of Leipzig, Leipzig, Germany.
Martin Luther University Halle-Wittenberg, Halle, Germany.
Arthritis Rheumatol. 2016 Feb;68(2):337-46. doi: 10.1002/art.39331.
Leukocyte immunoglobulin-like receptor 1 (LIR-1) is up-regulated by cytomegalovirus (CMV), which in turn, has been associated with premature aging and more severe joint disease in patients with rheumatoid arthritis (RA). The aim of this study was to investigate the expression and functional significance of LIR-1 in CMV-positive RA patients.
We determined the phenotype, cytolytic potential, CMV-specific proliferation, and HLA-G-triggered, LIR-1-mediated inhibition of interferon-γ secretion of LIR-1+ T cells in RA patients and healthy controls.
We found increased frequencies of CD8+ T cells with CMV pp65-specific T cell receptors in CMV-positive RA patients as compared to CMV-positive healthy controls. CMV-specific CD8+ T cells in these patients were preferentially LIR-1+ and exhibited a terminally differentiated polyfunctional phenotype. The numbers of LIR-1+CD8+ T cells increased with age and disease activity, and showed high levels of reactivity to CMV antigens. Ligation of LIR-1 with soluble HLA-G molecules in vitro confirmed an inhibitory role of the molecule when expressed on CD8+ T cells in RA patients.
We propose that latent CMV infection in the context of a chronic autoimmune response induces the recently described "chronic infection phenotype" in CD8+ T cells, which retains anti-infectious effector features while exhibiting autoreactive cytolytic potential. This response is likely dampened by LIR-1 to avoid overwhelming immunopathologic changes in the setting of the autoimmune disease RA. The known deficiency of soluble HLA-G in RA and the observed association of LIR-1 expression with disease activity suggest, however, that LIR-1+ T cells are insufficiently controlled in RA and are still likely to be involved in the pathogenesis of the disease.
白细胞免疫球蛋白样受体 1（LIR-1）可被巨细胞病毒（CMV）上调，而 CMV 反过来又与类风湿关节炎（RA）患者的过早衰老和更严重的关节疾病有关。本研究旨在探讨 CMV 阳性 RA 患者中 LIR-1 的表达及其功能意义。
我们确定了 RA 患者和健康对照者中 LIR-1+T 细胞的表型、细胞毒性潜能、CMV 特异性增殖以及 HLA-G 触发、LIR-1 介导的干扰素-γ分泌抑制作用。
与 CMV 阳性健康对照组相比，我们发现 CMV 阳性 RA 患者中 CD8+T 细胞具有 CMV pp65 特异性 T 细胞受体的频率增加。这些患者的 CMV 特异性 CD8+T 细胞优先为 LIR-1+，并表现出终末分化的多能表型。LIR-1+CD8+T 细胞的数量随着年龄和疾病活动度的增加而增加，并对 CMV 抗原表现出高反应性。体外 LIR-1 与可溶性 HLA-G 分子的结合证实了该分子在 RA 患者 CD8+T 细胞上表达时的抑制作用。
我们提出，慢性自身免疫反应背景下的潜伏性 CMV 感染诱导 CD8+T 细胞中最近描述的“慢性感染表型”，该表型保留了抗感染效应功能，同时表现出自身反应性细胞毒性潜能。这种反应可能被 LIR-1 抑制，以避免在自身免疫性疾病 RA 的背景下发生免疫病理变化。已知 RA 中可溶性 HLA-G 的缺乏以及观察到的 LIR-1 表达与疾病活动度的相关性表明，LIR-1+T 细胞在 RA 中未得到充分控制，并且仍可能参与疾病的发病机制。
