Responsiveness of HIV-specific CD4 T cells to PD-1 blockade
Responsiveness of HIV-specific CD4 T cells to PD-1 blockade
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DOI：
10.1182/blood-2010-12-328070
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发表时间：
2011-07-28
期刊：
影响因子：
20.3
通讯作者：
Kaufmann, Daniel E.
中科院分区：
文献类型：
--
作者：
Porichis, Filippos;Kwon, Douglas S.;Kaufmann, Daniel E.
定义程序性死亡-1（PD-1）损害的辅助性T细胞功能对于理解其在有缺陷的HIV控制中的作用以及确定靶向这种抑制途径的治疗潜力至关重要。我们在这里描述疾病阶段，PD-1表达水平和CD 4 T细胞损伤的可逆性之间的关系。体外PD-L1阻断增强了CD 4 T细胞对Th 0（IL-2）、Th 1（IFN-γ）、Th 2（IL-13）和TFH（IL-21）细胞因子的HIV特异性产生。PD-L1阻断导致细胞增殖前细胞因子转录和翻译的早期增加。尽管PD-L1阻断对细胞因子表达的影响以及较小程度上对细胞增殖的影响与疾病进展标志物相关，但在大多数病毒血症检测不到的受试者中也观察到细胞因子分泌恢复。PD-L1阻断可恢复PD-1中等和PD 1高分选的CD 4 T细胞亚群中的细胞因子分泌。与PD-1high HIV特异性CD 8 T细胞相似，PD-1high HIV特异性CD 4 T细胞显示抑制性分子CD 160和2B 4的表达较低，表明T细胞亚群之间抑制性受体的表达存在显著差异。这些数据表明，PD-1通过限制这些细胞的扩增和通过抑制多种分化的CD 4 T细胞亚群的效应子功能来损害HIV特异性T辅助细胞应答。（血。2011; 118（4）：965-974）
Defining the T helper functions impaired by programmed death-1 (PD-1) is crucial for understanding its role in defective HIV control and determining the therapeutic potential of targeting this inhibitory pathway. We describe here the relationships among disease stage, levels of PD-1 expression, and reversibility of CD4 T-cell impairment. PD-L1 blockade in vitro enhanced HIV-specific production of Th0 (IL-2), Th1 (IFN-gamma), Th2 (IL-13), and TFH (IL-21) cytokines by CD4 T cells. PD-L1 blockade caused an early increase in cytokine transcription and translation that preceded cell proliferation. Although the impact of PD-L1 blockade on cytokine expression and, to a lesser extent, cell proliferation was associated with markers of disease progression, restoration of cytokine secretion was also observed in most subjects with undetectable viremia. PD-L1 blockade restored cytokine secretion in both PD-1intermediate and PD1high sorted CD4 T-cell subsets. Com-pared with PD-1high HIV-specific CD8 T cells, PD-1high HIV-specific CD4 T cells showed lower expression of the inhibitory molecules CD160 and 2B4, demonstrating marked differences in expression of inhibitory receptors between T-cell subsets. These data show that PD-1 impairs HIV-specific T helper responses both by limiting expansion of these cells and by inhibiting effector functions of multiple differentiated CD4 T-cell subsets. (Blood. 2011; 118(4): 965-974)