PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression
PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression
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DOI：
10.1038/nature05115
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发表时间：
2006-09-21
期刊：
影响因子：
64.8
通讯作者：
Walker, Bruce D.
中科院分区：
文献类型：
--
作者：
Day, Cheryl L.;Kaufmann, Daniel E.;Walker, Bruce D.
T细胞的功能损害是许多慢性小鼠和人类病毒感染的特征。抑制性受体程序性死亡1（PD-1;也称为PDCD 1）是活化T细胞的负调节因子（1-4），在小鼠中耗竭的病毒特异性CD 8 T细胞表面上显著上调（5）。使用抗PD配体1（PD-L1，也称为CD 274）的抗体阻断该途径可恢复CD 8 T细胞功能并降低病毒载量（5）。为了研究PD-1在慢性人类病毒感染中的作用，我们使用10种主要组织相容性复合体（MHC）I类四聚体检测了71名未经抗HIV治疗的C分支感染者中人类免疫缺陷病毒（HIV）特异性CD 8 T细胞上的PD-1表达。在这里，我们报告PD-1在这些细胞上显著上调，并且表达与受损的HIV特异性CD 8 T细胞功能以及疾病进展的预测因子相关：与血浆病毒载量呈正相关，与CD 4 T细胞计数呈负相关。CD 4 T细胞上的PD-1表达同样与病毒载量呈正相关，与CD 4 T细胞计数呈负相关，阻断该途径可增强HIV特异性CD 4和CD 8 T细胞功能。这些数据表明，免疫调节PD-1/PD-L1途径在人类持续性病毒感染期间是有效的，并定义了HIV特异性T细胞功能的可逆缺陷。此外，这种可逆性T细胞损伤的途径为增强慢性HIV感染中耗尽的T细胞的功能提供了潜在的靶点。
Functional impairment of T cells is characteristic of many chronic mouse and human viral infections. The inhibitory receptor programmed death 1 (PD-1; also known as PDCD1), a negative regulator of activated T cells(1-4), is markedly upregulated on the surface of exhausted virus-specific CD8 T cells in mice(5). Blockade of this pathway using antibodies against the PD ligand 1 (PD-L1, also known as CD274) restores CD8 T-cell function and reduces viral load(5). To investigate the role of PD-1 in a chronic human viral infection, we examined PD-1 expression on human immunodeficiency virus (HIV)-specific CD8 T cells in 71 clade-C-infected people who were naive to anti-HIV treatments, using ten major histocompatibility complex (MHC) class I tetramers specific for frequently targeted epitopes. Here we report that PD-1 is significantly upregulated on these cells, and expression correlates with impaired HIV-specific CD8 T-cell function as well as predictors of disease progression: positively with plasma viral load and inversely with CD4 T-cell count. PD-1 expression on CD4 T cells likewise showed a positive correlation with viral load and an inverse correlation with CD4 T-cell count, and blockade of the pathway augmented HIV-specific CD4 and CD8 T-cell function. These data indicate that the immunoregulatory PD-1/PD-L1 pathway is operative during a persistent viral infection in humans, and define a reversible defect in HIV-specific T-cell function. Moreover, this pathway of reversible T-cell impairment provides a potential target for enhancing the function of exhausted T cells in chronic HIV infection.