Rheumatology Unit, Department of Medicine at Karolinska University Hospital, Karolinska Institute, Solna, Stockholm, Sweden.
Scand J Immunol. 2014 Feb;79(2):149-55. doi: 10.1111/sji.12139.
Proinflammatory CD4(+) CD28(null) T cells are frequently found in the circulation of patients with rheumatoid arthritis (RA), but are less common in the rheumatic joint. In the present study, we sought to identify functional differences between CD4(+) CD28(null) T cells from blood and synovial fluid in comparison with conventional CD28-expressing CD4(+) T cells. Forty-four patients with RA, displaying a distinct CD4(+) CD28(null) T cell population in blood, were recruited for this study; the methylation status of the IFNG locus was examined in isolated T cell subsets, and intracellular cytokine production (IFN-γ, TNF, IL-17) and chemokine receptor expression (CXCR3, CCR6 and CCR7) were assessed by flow cytometry on T cells from the two compartments. Circulating CD4(+) CD28(null) T cells were significantly more hypomethylated in the CNS-1 region of the IFNG locus than conventional CD4(+) CD28(+) T cells and produced higher levels of both IFN-γ and TNF after TCR cross-linking. CD4(+) CD28(null) T cells from the site of inflammation expressed significantly more CXCR3 and CCR6 compared to their counterparts in blood. While IL-17A production could hardly be detected in CD4(+) CD28(null) cells from the blood, a significant production was observed in CD4(+) CD28(null) T cells from synovial fluid. CD4(+) CD28(null) T cells were not only found to differ from conventional CD4(+) CD28(+) T cells in the circulation, but we could also demonstrate that synovial CD4(+) CD28(null) T cells showed additional effector functions (IL-17 coproduction) as compared to the same subset in peripheral blood, suggesting an active role for these cells in the perpetuation of inflammation in the subset of patients having a CD28(null) population.
促炎性 CD4(+) CD28(null) T 细胞经常在类风湿关节炎 (RA) 患者的循环中被发现，但在风湿关节中较少见。在本研究中，我们试图确定血液和滑液中 CD4(+) CD28(null) T 细胞与常规 CD28 表达的 CD4(+) T 细胞之间的功能差异。本研究招募了 44 名 RA 患者，他们的血液中存在明显的 CD4(+) CD28(null) T 细胞群体；在分离的 T 细胞亚群中检查了 IFNG 基因座的甲基化状态，并通过流式细胞术评估了这两个隔室中 T 细胞的细胞内细胞因子产生（IFN-γ、TNF、IL-17）和趋化因子受体表达（CXCR3、CCR6 和 CCR7）。与常规 CD4(+) CD28(+) T 细胞相比，循环 CD4(+) CD28(null) T 细胞在 IFNG 基因座的 CNS-1 区域明显呈低甲基化状态，并且在 TCR 交联后产生更高水平的 IFN-γ 和 TNF。炎症部位的 CD4(+) CD28(null) T 细胞表达的 CXCR3 和 CCR6 明显高于血液中的相应细胞。虽然在血液中的 CD4(+) CD28(null) 细胞中几乎检测不到 IL-17A 的产生，但在滑液中的 CD4(+) CD28(null) T 细胞中观察到显著的产生。CD4(+) CD28(null) T 细胞不仅在循环中与常规 CD4(+) CD28(+) T 细胞不同，我们还可以证明与外周血中的相同亚群相比，滑膜 CD4(+) CD28(null) T 细胞表现出额外的效应功能（IL-17 共产生），这表明这些细胞在 CD28(null) 群体患者的炎症持续存在中发挥了积极作用。
