Proliferating Transitory T Cells with an Effector-like Transcriptional Signature Emerge from PD-1+ Stem-like CD8+ T Cells during Chronic Infection
Proliferating Transitory T Cells with an Effector-like Transcriptional Signature Emerge from PD-1+ Stem-like CD8+ T Cells during Chronic Infection
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DOI：
10.1016/j.immuni.2019.11.002
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发表时间：
2019-12-17
期刊：
影响因子：
32.4
通讯作者：
Ahmed, Rafi
中科院分区：
文献类型：
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作者：
Hudson, William H.;Gensheimer, Julia;Ahmed, Rafi
T细胞功能障碍是慢性病毒感染和癌症的特征。最近对慢性淋巴细胞性脉络丛脑膜炎病毒（LCMV）感染的研究已经定义了一个PD-1(+) Tcf-1(+) CD8(+) T细胞亚群，能够自我更新并分化为更终分化的细胞，下调Tcf-1并表达额外的抑制分子，如Tim3。在这里，我们证明了糖蛋白CD101的表达将这种终末分化的群体分为两个亚群。干细胞样Tcf-1(+) CD8(+) T细胞最初分化为CD101 Tim3（+）细胞的短暂群体，随后转化为CD101(+) Tim3+细胞。最近生成的CD101 Tim3（+）细胞在体内增殖，有助于病毒控制，并以效应样转录特征为标志，包括趋化因子受体CX3CR1、促炎细胞因子和颗粒酶b的表达。PD-1途径阻断增加了CD101 Tim3(+) CD8(+) T细胞的数量，表明这些新生成的移行细胞在PD-1免疫治疗中起关键作用。
T cell dysfunction is a characteristic feature of chronic viral infection and cancer. Recent studies in chronic lymphocytic choriomeningitis virus (LCMV) infection have defined a PD-1(+) Tcf-1(+) CD8(+) T cell subset capable of self-renewal and differentiation into more terminally differentiated cells that downregulate Tcf-1 and express additional inhibitory molecules such as Tim3. Here, we demonstrated that expression of the glycoprotein CD101 divides this terminally differentiated population into two subsets. Stem-like Tcf-1(+) CD8(+) T cells initially differentiated into a transitory population of CD101 Tim3(+) cells that later converted into CD101(+) Tim3+ cells. Recently generated CD101 Tim3(+) cells proliferated in vivo, contributed to viral control, and were marked by an effector-like transcriptional signature including expression of the chemokine receptor CX3CR1, pro-inflammatory cytokines, and granzyme B. PD-1 pathway blockade increased the numbers of CD101 Tim3(+) CD8(+) T cells, suggesting that these newly generated transitional cells play a critical role in PD-1-based immunotherapy.