Defining CD8+ T cells that provide the proliferative burst after PD-1 therapy.
Defining CD8+ T cells that provide the proliferative burst after PD-1 therapy.
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DOI：
10.1038/nature19330
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发表时间：
2016-09-15
期刊：
影响因子：
64.8
通讯作者：
Ahmed R
中科院分区：
文献类型：
--
作者：
Im SJ;Hashimoto M;Gerner MY;Lee J;Kissick HT;Burger MC;Shan Q;Hale JS;Lee J;Nasti TH;Sharpe AH;Freeman GJ;Germain RN;Nakaya HI;Xue HH;Ahmed R
慢性病毒感染的特征是CD8+T细胞功能障碍，这与程序性细胞死亡1(PD-1)抑制受体的表达有关。需要更好地了解在慢性感染过程中调节CD8+T细胞反应的机制，以改进免疫疗法，恢复耗尽的CD8+T细胞的功能。在这里，我们确定了一组病毒特异性的CD8+T细胞，它们在慢性感染淋巴细胞性脉络膜脑膜炎病毒(LCMV)的小鼠的PD-1抑制通路被阻断后增殖。这些LCMV特异性CD8+T细胞表达PD-1抑制受体，但也表达几种共刺激分子，如ICOS和CD28。CD8+T细胞亚群具有独特的基因特征，与CD4+T滤泡辅助(TFH)细胞、CD8+T细胞记忆前体细胞和造血祖细胞相关，但不同于CD4+TH1细胞和CD8+末端效应细胞。CD8+T细胞群仅见于淋巴组织，主要分布于T细胞区和幼稚CD8+T细胞。这些PD-1+CD8+T细胞类似于慢性LCMV感染期间的干细胞，经历自我更新，并分化为终末耗尽的CD8+T细胞，存在于淋巴组织和非淋巴组织中。PD-1阻断后的增殖爆发几乎完全来自CD8+T细胞亚群。值得注意的是，转录因子TCF1在CD8+T细胞亚群的产生中具有细胞固有的和必不可少的作用。这些发现提供了对T细胞耗竭的更好的理解，并对PD-1导向的免疫疗法在慢性感染和癌症中的优化具有指导意义。
Chronic viral infections are characterized by a state of CD8+ T-cell dysfunction that is associated with expression of the programmed cell death 1 (PD-1) inhibitory receptor. A better understanding of the mechanisms that regulate CD8+ T cell responses during chronic infection is required to improve immunotherapies that restore function in exhausted CD8+ T cells. Here we identify a population of virus-specific CD8+ T cells that proliferate after blockade of the PD-1 inhibitory pathway in mice chronically infected with lymphocytic choriomeningitis virus (LCMV). These LCMV-specific CD8+ T cells expressed the PD-1 inhibitory receptor but also expressed several costimulatory molecules such as ICOS and CD28. This CD8+ T cell subset was characterized by a unique gene signature that was related to that of CD4+ T follicular helper (TFH) cells, CD8+ T cell memory precursors and haematopoietic stem cell progenitors, but that was distinct from that of CD4+ TH1 cells and CD8+ terminal effectors. This CD8+ T cell population was found only in lymphoid tissues and resided predominantly in the T cell zones along with naïve CD8+ T cells. These PD-1+ CD8+ T cells resembled stem cells during chronic LCMV infection, undergoing self-renewal and also differentiating into the terminally exhausted CD8+ T cells that were present in both lymphoid and non-lymphoid tissues. The proliferative burst after PD-1 blockade came almost exclusively from this CD8+ T cell subset. Notably, the transcription factor TCF1 had a cell intrinsic and essential role in the generation of this CD8+ T cell subset. These findings provide a better understanding of T cell exhaustion and have implications in the optimization of PD-1-directed immunotherapy in chronic infections and cancer.