CD4+ T Cell Help Is Required for the Formation of a Cytolytic CD8+ T Cell Subset that Protects against Chronic Infection and Cancer
CD4+ T Cell Help Is Required for the Formation of a Cytolytic CD8+ T Cell Subset that Protects against Chronic Infection and Cancer
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DOI：
10.1016/j.immuni.2019.10.009
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发表时间：
2019-12-17
期刊：
影响因子：
32.4
通讯作者：
Cui, Weiguo
中科院分区：
文献类型：
--
作者：
Zander, Ryan;Schauder, David;Cui, Weiguo
尽管CD4(+)T细胞对维持抗病毒免疫至关重要，但在慢性感染过程中，CD4(+)T细胞调节CD8(+)T细胞分化的机制仍不清楚。在这里，使用单细胞RNA测序，我们表明CD8(+)T细胞对慢性感染的反应比以前所认识的更具异质性。重要的是，我们的发现揭示了表达CX(3)CR1的CD8(+)T细胞亚群的形成，该亚群具有强大的细胞溶解功能，是病毒控制所必需的。值得注意的是，我们的数据进一步表明，这一细胞毒亚群的形成严重依赖于通过白介素21(IL-21)的CD4(+)T细胞的帮助，开发这一发育途径可以用于治疗，以增强CD8(+)T细胞渗透到肿瘤中的杀伤功能。这些发现揭示了“CD4(+)T细胞帮助”如何在持续感染期间调节CD8(+)T细胞分化的更多分子机制，并对优化免疫治疗中保护性CD8(+)T细胞的生成具有指导意义。
Although CD4(+) T cell "help" is crucial to sustain antiviral immunity, the mechanisms by which CD4(+) T cells regulate CD8(+) T cell differentiation during chronic infection remain elusive. Here, using single-cell RNA sequencing, we show that CD8(+) T cells responding to chronic infection were more heterogeneous than previously appreciated. Importantly, our findings uncovered the formation of a CX(3)CR1-expressing CD8(+) T cell subset that exhibited potent cytolytic function and was required for viral control. Notably, our data further demonstrate that formation of this cytotoxic subset was critically dependent on CD4(+) T cell help via interleukin-21 (IL-21) and that exploitation of this developmental pathway could be used therapeutically to enhance the killer function of CD8(+) T cells infiltrated into the tumor. These findings uncover additional molecular mechanisms of how "CD4(+) T cell help" regulates CD8(+) T cell differentiation during persistent infection and have implications toward optimizing the generation of protective CD8(+) T cells in immunotherapy.