PD-1 is imprinted on cytomegalovirus-specific CD4+ T cells and attenuates Th1 cytokine production whilst maintaining cytotoxicity.
PD-1 is imprinted on cytomegalovirus-specific CD4+ T cells and attenuates Th1 cytokine production whilst maintaining cytotoxicity.
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PD-1在巨细胞病毒特异性CD 4 + T细胞上印迹，并减弱Th 1细胞因子的产生，同时保持细胞毒性。
DOI：
10.1371/journal.ppat.1009349
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发表时间：
2021-03
期刊：
影响因子：
6.7
通讯作者：
Moss P
中科院分区：
文献类型：
--
作者：
Parry HM;Dowell AC;Zuo J;Verma K;Kinsella FAM;Begum J;Croft W;Sharma-Oates A;Pratt G;Moss P
PD-1在癌症患者的耗尽的T细胞上表达，但其生理作用仍不确定。我们确定了潜伏感染期间巨细胞病毒特异性CD 4 + T细胞上PD-1表达的表型、功能和转录相关性。PD-1表达范围为10-85%，在个体供体中随时间保持稳定。这个“设定点”与初次感染时的病毒载量相关。PD-1+ CD 4 + T细胞显示出强的细胞毒性功能，但产生低水平的Th 1细胞因子，其仅被PD-1阻断部分逆转。TCR克隆型显示PD-1+和PD-1-CMV特异性细胞之间的可变共享，表明PD-1状态在T细胞引发或随后的克隆扩增期间定义。因此，生理性PD-1+ CD 4 + T细胞显示出独特的“高细胞毒性-低细胞因子”表型，并且可以起到抑制病毒再活化的作用，同时使组织炎症最小化。进一步了解PD-1的生理作用将有助于阐明恶性疾病患者PD-1+ CD 4 + T细胞耗竭的机制和潜在逆转。PD-1由CMV特异性CD 4 T细胞亚群表达，我们显示表达与活化或“耗竭”无关。我们继续显示PD-1+池的大小在初次感染时建立，并且表达在抗原特异性细胞群和单个细胞上保持稳定，表明表达是印记的并由“设定点”控制。表达PD-1的CD 4 T细胞包含具有强细胞毒性但细胞因子产生减少的细胞，其可用于抑制病毒再活化，同时使组织炎症最小化。
PD-1 is expressed on exhausted T cells in cancer patients but its physiological role remains uncertain. We determined the phenotype, function and transcriptional correlates of PD-1 expression on cytomegalovirus-specific CD4+ T cells during latent infection. PD-1 expression ranged from 10–85% and remained stable over time within individual donors. This ‘setpoint’ was correlated with viral load at primary infection. PD-1+ CD4+ T cells display strong cytotoxic function but generate low levels of Th1 cytokines which is only partially reversed by PD-1 blockade. TCR clonotypes showed variable sharing between PD-1+ and PD-1- CMV-specific cells indicating that PD-1 status is defined either during T cell priming or subsequent clonal expansion. Physiological PD-1+ CD4+ T cells therefore display a unique ‘high cytotoxicity-low cytokine’ phenotype and may act to suppress viral reactivation whilst minimizing tissue inflammation. Improved understanding of the physiological role of PD-1 will help to delineate the mechanisms, and potential reversal, of PD-1+ CD4+ T cell exhaustion in patients with malignant disease. PD-1 is expressed by a subset of CMV-specific CD4 T cells, we show expression is not associated with activation or ‘exhaustion’. We go onto show the size of the PD-1+ pool is established at primary infection, and expression remains stable on antigen specific cell populations and on individual cells, indicating expression is imprinted and controlled by a ‘set point’. PD-1 expressing CD4 T cells comprise cells with strong cytotoxicity but reduced cytokine production which may act to suppress viral reactivation whilst minimizing tissue inflammation.