TOX is expressed by exhausted and polyfunctional human effector memory CD8+ T cells
TOX is expressed by exhausted and polyfunctional human effector memory CD8+ T cells
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DOI：
10.1126/sciimmunol.aba7918
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发表时间：
2020-07-01
影响因子：
24.8
通讯作者：
Buggert, Marcus
中科院分区：
文献类型：
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作者：
Sekine, Takuya;Perez-Potti, Andre;Buggert, Marcus
CD8(+) T细胞衰竭是许多癌症和慢性感染的标志。在小鼠中，T细胞因子1 （TCF-1）维持耗尽的CD8(+) T细胞应答，而胸腺细胞选择相关的HMG盒（TOX）是耗尽的CD8(+) T细胞表观遗传重塑和存活所必需的。然而，目前尚不清楚这些转录因子在多大程度上在人类中发挥类似的作用。在这项研究中，我们绘制了TOX和TCF-1的表达，作为人类CD8(+) T细胞景观分化和特异性的功能。在这里，我们证明循环TOX+ CD8(+) T细胞存在于大多数人类中，但TOX并不完全与疲惫相关。效应记忆CD8(+) T细胞通常表达TOX，而幼稚和早期分化记忆CD8(+) T细胞通常表达TCF-1。细胞溶解基因和蛋白的表达特征也由TOX的表达来确定。在无情的免疫挑战背景下，耗尽的hiv特异性CD8(+) T细胞通常表达TOX，通常聚集在具有各种激活标记和抑制受体的簇中，并且表达较少的TCF-1。然而，巨细胞病毒（CMV）或eb病毒（EBV）特异性的多功能记忆CD8(+) T细胞也表达TOX，无论是否含有TCF-1。在hiv特异性CD8(+) T细胞中观察到类似的表型，这些细胞来自对病毒复制保持异常免疫控制的个体。总的来说，这些数据表明TOX是由大多数循环效应记忆CD8(+) T细胞亚群表达的，并不完全与衰竭有关。
CD8(+) T cell exhaustion is a hallmark of many cancers and chronic infections. In mice, T cell factor 1 (TCF-1) maintains exhausted CD8(+) T cell responses, whereas thymocyte selection-associated HMG box (TOX) is required for the epigenetic remodeling and survival of exhausted CD8(+) T cells. However, it has remained unclear to what extent these transcription factors play analogous roles in humans. In this study, we mapped the expression of TOX and TCF-1 as a function of differentiation and specificity in the human CD8(+) T cell landscape. Here, we demonstrate that circulating TOX+ CD8(+) T cells exist in most humans, but that TOX is not exclusively associated with exhaustion. Effector memory CD8(+) T cells generally expressed TOX, whereas naive and early-differentiated memory CD8(+) T cells generally expressed TCF-1. Cytolytic gene and protein expression signatures were also defined by the expression of TOX. In the context of a relentless immune challenge, exhausted HIV-specific CD8(+) T cells commonly expressed TOX, often in clusters with various activation markers and inhibitory receptors, and expressed less TCF-1. However, polyfunctional memory CD8(+) T cells specific for cytomegalovirus (CMV) or Epstein-Barr virus (EBV) also expressed TOX, either with or without TCF-1. A similar phenotype was observed among HIV-specific CD8(+) T cells from individuals who maintained exceptional immune control of viral replication. Collectively, these data demonstrate that TOX is expressed by most circulating effector memory CD8(+) T cell subsets and not exclusively linked to exhaustion.