BCL6-dependent TCF-1+ progenitor cells maintain effector and helper CD4 T cell responses to persistent antigen [ATAC-Seq]. BCL6-dependent TCF-1+ progenitor cells maintain effector and helper CD4 T cell responses to persistent antigen [ATAC-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+PD1+ T splenocytes were sorted and subjected to single-cell ATAC-seq on the 10x Genomics platform.

初次免疫致敏后不久，活化的CD4阳性T细胞（activated CD4 T cells）的命运会定向分化为BCL6阳性的滤泡辅助性T细胞（follicular helper T，Tfh）与BCL6阴性的效应性T细胞（effector T cells，Teff）。然而，在慢性抗原刺激条件下，这些细胞亚群如何维持稳态，目前仍未明确。本研究联合单细胞与群体水平研究手段，证实慢性病毒感染状态下，活化的CD4阳性T细胞可分化为依赖BCL6的TCF-1阳性祖细胞；这类祖细胞具备优异的扩增能力，且可分化为效应性T细胞与滤泡辅助性T细胞两类细胞。该类祖细胞与耗竭型CD8阳性T细胞的祖细胞亚群具有共通特性，且在抗原持续存在时，是效应性T细胞持续产生的必要条件。在肿瘤刺激情境下，引流淋巴结中亦可形成类似的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释了其群体动态变化规律。实验整体设计：分选CD4阳性、PD1阳性的脾脏T细胞（CD4+PD1+ T splenocytes），并在10x Genomics平台上开展单细胞ATAC测序（single-cell ATAC-seq）实验。