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 CX3CR1-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.

中文翻译：

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CD4 + T细胞帮助对于防止慢性感染和癌症的细胞溶解CD8 + T细胞亚群的形成是必需的。

尽管CD4 + T细胞的“帮助”对于维持抗病毒免疫至关重要，但是在慢性感染期间CD4 + T细胞调节CD8 + T细胞分化的机制仍然难以捉摸。在这里，使用单细胞RNA测序，我们显示响应慢性感染的CD8 + T细胞比以前意识到的异质性更高。重要的是，我们的发现揭示了表达CX3CR1的CD8 + T细胞亚群的形成，该亚群表现出强大的溶细胞功能，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，这种细胞毒性亚群的形成严重依赖于白介素21（IL-21）的CD4 + T细胞帮助，并且对该发育途径的开发可用于治疗性地增强浸润的CD8 + T细胞的杀伤功能。进入肿瘤。