本期文章：《自然—免疫学》：Online/在线发表

美国德克萨斯大学西南医学中心Tuoqi Wu等研究人员合作发现，FOXP1和KLF2相互调控CAR T细胞中干细胞样到效应转变的检查点。该研究于2023年11月27日在线发表于国际一流学术期刊《自然—免疫学》。

通过同时分析同一嵌合抗原受体（CAR）T细胞细胞的单细胞染色质可及性和转录组，研究人员发现了CD8+ T细胞亚群中的异质性染色质状态，这些状态预示着转录变化，并受到不同转录因子的调控。控制每个CD8+ T细胞亚群的转录因子都受到大量增强子的调控，并被定位为基因网络的枢纽。FOXP1是干细胞样网络的枢纽，它促进了CAR T细胞的扩增和干性，并限制了效应细胞的过度分化。在效应细胞网络中，KLF2能促进效应CD8+ T细胞分化，防止终末衰竭。因此，研究人员确定了控制干细胞样CD8+ CAR T细胞分化为效应细胞或衰竭CD8+ CAR T细胞的基因网络和中枢转录因子。

据介绍，在癌症和感染中，自我更新的干细胞样CD8+ T细胞可介导免疫疗法的反应，并补充终末衰竭的T细胞和效应样T细胞。然而，管理CAR T细胞系谱选择的程序尚不清楚。

附：英文原文

Title: FOXP1 and KLF2 reciprocally regulate checkpoints of stem-like to effector transition in CAR T cells

Author: Zhu, Ziang, Lou, Guohua, Teng, Xiao-Lu, Wang, Haixia, Luo, Ying, Shi, Wangke, Yihunie, Kiddist, Hao, Shumeng, DeGolier, Kole, Liao, Chengheng, Huang, Huocong, Zhang, Qing, Fry, Terry, Wang, Tao, Yao, Chen, Wu, Tuoqi

Issue&Volume: 2023-11-27

Abstract: In cancer and infections, self-renewing stem-like CD8+ T cells mediate the response of immunotherapies and replenish terminally exhausted T cells and effector-like T cells. However, the programs governing the lineage choice in chimeric antigen receptor (CAR) T cells are unclear. Here, by simultaneously profiling single-cell chromatin accessibility and transcriptome in the same CAR T cells, we identified heterogeneous chromatin states within CD8+ T cell subsets that foreshadowed transcriptional changes and were primed for regulation by distinct transcription factors. Transcription factors that controlled each CD8+ T cell subset were regulated by high numbers of enhancers and positioned as hubs of gene networks. FOXP1, a hub in the stem-like network, promoted expansion and stemness of CAR T cells and limited excessive effector differentiation. In the effector network, KLF2 enhanced effector CD8+ T cell differentiation and prevented terminal exhaustion. Thus, we identified gene networks and hub transcription factors that controlled the differentiation of stem-like CD8+ CAR T cells into effector or exhausted CD8+ CAR T cells.

DOI: 10.1038/s41590-023-01685-w