CD39 Expression Identifies Terminally Exhausted CD8+ T Cells

Exhausted T cells express multiple co-inhibitory molecules that impair their function and limit immunity to chronic viral infection. Defining novel markers of exhaustion is important both for identifying and potentially reversing T cell exhaustion. Herein, we show that the ectonucleotidse CD39 is a marker of exhausted CD8+ T cells. CD8+ T cells specific for HCV or HIV express high levels of CD39, but those specific for EBV and CMV do not. CD39 expressed by CD8+ T cells in chronic infection is enzymatically active, co-expressed with PD-1, marks cells with a transcriptional signature of T cell exhaustion and correlates with viral load in HIV and HCV. In the mouse model of chronic Lymphocytic Choriomeningitis Virus infection, virus-specific CD8+ T cells contain a population of CD39high CD8+ T cells that is absent in functional memory cells elicited by acute infection. This CD39high CD8+ T cell population is enriched for cells with the phenotypic and functional profile of terminal exhaustion. These findings provide a new marker of T cell exhaustion, and implicate the purinergic pathway in the regulation of T cell exhaustion.耗竭性T细胞（Exhausted T cells）可表达多种共抑制分子，这些分子会损害其功能并限制机体针对慢性病毒感染的免疫应答能力。鉴定T细胞耗竭的新型标志物，对于识别该细胞群体乃至潜在逆转T细胞耗竭状态均具有重要意义。本研究证实，胞外核苷酸酶CD39可作为耗竭性CD8+ T细胞的标志物。针对HCV（丙型肝炎病毒）或HIV（人类免疫缺陷病毒）的CD8+ T细胞可高表达CD39，而针对EBV（EB病毒）与CMV（巨细胞病毒）的CD8+ T细胞则无此表达特征。慢性感染环境下CD8+ T细胞所表达的CD39具备酶学活性，可与PD-1（程序性死亡受体1）共表达，能够标识具有T细胞耗竭转录特征的细胞群体，且与HIV及HCV感染者的病毒载量呈显著相关性。在慢性淋巴细胞性脉络丛脑膜炎病毒（Lymphocytic Choriomeningitis Virus）感染的小鼠模型中，病毒特异性CD8+ T细胞中存在CD39high CD8+ T细胞亚群，而急性感染诱导产生的功能性记忆细胞中并不存在此类亚群。该CD39high CD8+ T细胞亚群中富含呈现终末耗竭表型与功能特征的细胞。本研究发现为T细胞耗竭提供了全新的标志物，并提示嘌呤能通路参与调控T细胞耗竭过程。