PD-1 expression and IL-2 loss of cytomegalovirus-specific T cells correlates with viremia and reversible functional anergy
PD-1 expression and IL-2 loss of cytomegalovirus-specific T cells correlates with viremia and reversible functional anergy
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DOI：
10.1111/j.1600-6143.2008.02279.x
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发表时间：
2008-07-01
影响因子：
8.8
通讯作者：
Sester, M.
中科院分区：
文献类型：
--
作者：
Sester, U.;Presser, D.;Sester, M.
巨细胞病毒（CMV）是移植后感染性并发症的主要原因。最近，淋巴细胞脉络丛脑膜炎病毒（LCMV）、HIV或HCV的慢性感染显示与功能衰竭的T细胞相关，其特征在于程序性死亡（PD）-1分子的高表达和改变的细胞因子表达模式。因此，我们假设CMV特异性CD 4 T细胞的功能衰竭可能决定肾移植后患者CMV控制受损。在病毒血症移植受者中，与非病毒血症移植患者（8.8%，0.8-80.5%）、透析患者（8.8%，0-36.7%）或对照组（3.2%，0.3- 15.4%，p < 0.0001）相比，CMV特异性CD 4 T细胞PD-1阳性的比例显著更高（中位数40.9%，17.0-88.7%）。与功能损伤一致，与PD-1阴性T细胞相比，PD-1阳性T细胞产生显著更少的IFN γ（p < 0.0001）。此外，与对照或非病毒血症患者不同，来自病毒血症患者的CMV特异性T细胞显示出IL-2产生的显著损失（p < 0.0001）。有趣的是，CMV特异性CD 4 T细胞的功能性无反应性是可逆的，因为抗体介导的用其配体PD-L1/-L2阻断PD-1信号传导导致CMV特异性增殖增加高达10倍。总之，PD-1的表达定义了与病毒血症相关的CMV特异性CD 4 T细胞的可逆性缺陷，阻断PD-1信号传导可能为增强慢性CMV感染中耗尽的T细胞的功能提供潜在的靶点。
Cytomegalovirus (CMV) represents a major cause of infectious complications after transplantation. Recently, chronic infections with lymphocyte choriomeningitis virus (LCMV), HIV or HCV were shown to be associated with functionally exhausted T cells characterized by high expression of the programmed death (PD)-1 molecule and altered cytokine expression patterns. We therefore hypothesized that functional exhaustion of CMV-specific CD4 T cells may determine impaired CMV control in patients after renal transplantation. In viremic transplant recipients, a significantly higher proportion of CMV-specific CD4 T cells was PD-1 positive (median 40.9%, 17.0-88.7%) as compared to nonviremic transplant patients (8.8%, 0.8-80.5%), dialysis patients (8.8%, 0-36.7%) or controls (3.2%, 0.3-15.4%, p < 0.0001). In line with functional impairment, PD-1-positive T cells produced significantly less IFN gamma as compared to PD-1-negative T cells (p < 0.0001). Moreover, unlike controls or nonviremic patients, CMV-specific T cells from viremic patients showed a significant loss of IL-2 production (p < 0.0001). Interestingly, functional anergy of CMV-specific CD4 T cells was reversible in that antibody-mediated blockade of PD-1 signaling with its ligands PD-L1/-L2 led to an up to 10-fold increase in CMV-specific proliferation. In conclusion, expression of PD-1 defines a reversible defect of CMV-specific CD4 T cells that is associated with viremia, and blocking PD-1 signaling may provide a potential target for enhancing the function of exhausted T cells in chronic CMV infection.