BCL6-dependent TCF-1+ progenitor cells maintain effector and helper CD4 T cell responses to persistent antigen [scRNA-Seq]

Shortly after priming, the fate of activated CD4 T cells is segregated into BCL6+ follicular helper T (Tfh) and BCL6– effector (Teff) cells. However, it remains unknown how these subsets are sustained in the presence of chronic antigen stimulation. Using a combination of single cell- and population-based approaches, we show that in chronic viral infection, activated CD4 T cells differentiate into BCL6-dependent TCF-1+ progenitor cells with superior capacity to expand and give rise to both Teff and Tfh. They share properties with progenitor-exhausted CD8 T cells and are required for the continued generation of Teff cells as antigen persists. In response to tumors, an analogous CD4 T cell population develops in draining lymph nodes. Our study reveals the heterogeneity and plasticity of CD4 T cells upon encountering persistent antigen and highlights their population dynamics through a stable bipotent intermediate state. Overall design: CD4+ T splenocytes were sorted with I-Ab-LCMV-gp66 tetramer and subjected to paired single-cell RNA- and TCR-sequencing on the 10x Genomics platform.

在初次致敏后不久，活化的CD4阳性T细胞的发育命运会分化为BCL6阳性的滤泡辅助性T细胞（Tfh）与BCL6阴性的效应性T细胞（Teff）。然而，在慢性抗原刺激条件下，这些细胞亚群如何得以维持仍未可知。本研究结合单细胞与群体水平分析手段，发现在慢性病毒感染过程中，活化的CD4阳性T细胞会分化为依赖BCL6的TCF1阳性祖细胞，这类祖细胞具备更强的扩增能力，并可分化为Teff与Tfh两类细胞。这类细胞与祖细胞耗竭型CD8阳性T细胞具有相似的特性，且在抗原持续存在时，是持续生成Teff细胞所必需的。在肿瘤免疫应答中，引流淋巴结内也会形成类似的CD4阳性T细胞亚群。本研究揭示了CD4阳性T细胞在遭遇持续性抗原时的异质性与可塑性，并通过稳定的双潜能中间状态阐明了其群体动态变化规律。实验整体设计：通过I-Ab-LCMV-gp66四聚体分选CD4阳性脾脏淋巴细胞，并在10x Genomics平台上开展配对单细胞RNA测序与T细胞受体（TCR）测序。