Department of Transplant and Infection Immunology, Saarland University, Homburg, Germany.
Am J Transplant. 2013 Dec;13(12):3132-41. doi: 10.1111/ajt.12480. Epub 2013 Oct 22.
Expression of the inhibitory receptor programmed death 1 (PD-1) on cytomegalovirus (CMV)-specific CD4 T cells defines a phenotype associated with CMV viremia in transplant recipients. Moreover, CD28(-) CD27(-) double negativity is known as a typical phenotype of CMV-specific CD4 T cells. Therefore, the co-expression of inhibitory receptors on CD28(-) CD27(-) CD4 T cells was assessed as a rapid, stimulation-independent parameter for monitoring CMV complications after transplantation. Ninety-three controls, 67 hemodialysis patients and 81 renal transplant recipients were recruited in a cross-sectional and longitudinal manner. CMV-specific CD4 T cell levels quantified after stimulation were compared to levels of CD28(-) CD27(-) CD4 T cells. PD-1 and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) expression on CD28(-) CD27(-) CD4 T cells were related to viremia. A percentage of ≥0.44% CD28(-) CD27(-) CD4 T cells defined CMV seropositivity (93.3% sensitivity, 97.1% specificity), and their frequencies correlated strongly with CMV-specific CD4 T cell levels after stimulation (r = 0.73, p < 0.0001). Highest PD-1 expression levels on CD28(-) CD27(-) CD4 T cells were observed in patients with primary CMV viremia and reactivation (p < 0.0001), whereas CTLA-4 expression was only elevated during primary CMV viremia (p < 0.05). Longitudinal analysis showed a significant increase in PD-1 expression in relation to viremia (p < 0.001), whereas changes in nonviremic patients were nonsignificant. In conclusion, increased PD-1 expression on CD28(-) CD27(-) CD4 T cells correlates with CMV viremia in transplant recipients and may serve as a specific, stimulation-independent parameter to guide duration of antiviral therapy.
抑制性受体程序性死亡受体 1（PD-1）在巨细胞病毒（CMV）特异性 CD4 T 细胞上的表达定义了与移植受者 CMV 病毒血症相关的表型。此外，CD28（-）CD27（-）双阴性被认为是 CMV 特异性 CD4 T 细胞的典型表型。因此，评估抑制性受体在 CD28（-）CD27（-）CD4 T 细胞上的共表达作为移植后监测 CMV 并发症的一种快速、非刺激依赖性参数。采用横断面和纵向研究方法，共招募了 93 名对照者、67 名血液透析患者和 81 名肾移植受者。比较刺激后 CMV 特异性 CD4 T 细胞水平与 CD28（-）CD27（-）CD4 T 细胞水平。CD28（-）CD27（-）CD4 T 细胞上 PD-1 和细胞毒性 T 淋巴细胞相关抗原 4（CTLA-4）的表达与病毒血症有关。定义 CMV 血清阳性的 CD28（-）CD27（-）CD4 T 细胞百分比≥0.44%（93.3%的敏感性，97.1%的特异性），其频率与刺激后 CMV 特异性 CD4 T 细胞水平强烈相关（r = 0.73，p < 0.0001）。在原发性 CMV 病毒血症和再激活的患者中观察到 CD28（-）CD27（-）CD4 T 细胞上最高的 PD-1 表达水平（p < 0.0001），而 CTLA-4 表达仅在原发性 CMV 病毒血症期间升高（p < 0.05）。纵向分析显示，与病毒血症相关的 PD-1 表达显著增加（p < 0.001），而非病毒血症患者的变化无统计学意义。总之，CD28（-）CD27（-）CD4 T 细胞上 PD-1 表达的增加与移植受者的 CMV 病毒血症相关，可作为指导抗病毒治疗持续时间的一种特定、非刺激依赖性参数。
