Memory CD4+ T cells mediate long-term immunity, and their generation is a key objective of vaccination strategies. However, the transcriptional circuitry controlling the emergence of memory cells from early CD4+ antigen-responders remains poorly understood. Here, using single-cell RNA-seq to study the transcriptome of virus-specific CD4+ T cells, we identified a gene signature that distinguishes potential memory precursors from effector cells. We found that both that signature and the emergence of memory CD4+ T cells required the transcription factor Thpok. We further demonstrated that Thpok cell-intrinsically protected memory cells from a dysfunctional, effector-like transcriptional program, similar to but distinct from the exhaustion pattern of cells responding to chronic infection. Mechanistically, Thpok- bound genes encoding the transcription factors Blimp1 and Runx3 and acted by antagonizing their expression. Thus, a Thpok-dependent circuitry promotes both memory CD4+ T cells' differentiation and functional fitness, two previously unconnected critical attributes of adaptive immunity.

中文翻译：

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记忆CD4 + T细胞的出现和功能适应性需要转录因子Thpok。

记忆CD4 + T细胞可调节长期免疫力，其生成是疫苗接种策略的主要目标。然而，控制早期CD4 +抗原反应者的记忆细胞出现的转录途径仍然知之甚少。在这里，我们使用单细胞RNA-seq研究病毒特异性CD4 + T细胞的转录组，我们鉴定了一个基因标记，可将潜在的记忆前体与效应细胞区分开。我们发现该签名和记忆CD4 + T细胞的出现都需要转录因子Thpok。我们进一步证明了Thpok细胞本能地保护记忆细胞免受功能异常的，类似效应子的转录程序的侵害，类似于但不同于对慢性感染作出反应的细胞衰竭模式。机械上，Thpok结合的基因编码转录因子Blimp1和Runx3，并通过拮抗它们的表达起作用。因此，依赖Thpok的电路可同时促进记忆CD4 + T细胞的分化和功能适应性，这是适应性免疫的两个先前未连接的关键属性。