美国加州大学Wei Wang团队的最新研究提出了Atlas引导的T细胞编程转录因子的发现。相关论文于2026年2月4日发表在《自然》杂志上。

为了系统地定义驱动这些状态的转录因子（TFs），研究人员构建了一个综合图谱，整合了9个CD8+ T细胞状态和推断的TF活动谱。他们的分析对TF活性指纹进行了分类，揭示了控制选择性细胞状态分化的调节机制。利用这一平台，研究人员将重点放在两种转录相似但功能相反的状态上，这两种状态在肿瘤和病毒环境中至关重要：（TEXterm）细胞，功能失调的和组织驻留记忆T（TRM）细胞，具有保护作用。全球TF群落分析揭示了不同的生物学途径和TF驱动网络在保护和功能失调状态下的作用。

通过结合单细胞RNA测序（in vivo Perturb-seq）的体内CRISPR筛选，课题组人员描绘了几种选择性控制长期细胞分化的TFs。课题组研究人员还发现HIC1和GFI1是TEXterm和TRM细胞分化的共同调节因子，KLF6是TRM细胞的独特调节因子。研究小组发现了新的TEXterm选择性TFs，包括ZSCAN20和JDP2，它们以前在T细胞中没有已知的功能。靶向删除这些TFs增强了对肿瘤的控制，并与免疫检查点阻断协同作用，但不干扰TRM细胞的形成。一直以来，它们在人类T细胞减少抑制受体的表达，提高效应功能。通过将耗尽TEX选择性与保护性TRM细胞程序解耦，他们的平台能够更精确地设计T细胞状态，加速更有效的细胞免疫疗法的合理设计。

据了解，CD8+ T 在癌症和慢性感染中，细胞分化成不同的状态，形成免疫结果。

附：英文原文

Title: Atlas-guided discovery of transcription factors for T cell programming

Author: Chung, H. Kay, Liu, Cong, Battu, Anamika, Jambor, Alexander N., Pratt, Brandon M., Xie, Fucong, Riesenberg, Brian P., Casillas, Eduardo, Sun, Ming, Landoni, Elisa, Li, Yanpei, Ye, Qidang, Joo, Daniel, Green, Jarred, Syed, Zaid, Brown, Nolan J., Smith, Matthew, Ma, Shixin, Tan, Shirong, Chick, Brent, Tripple, Victoria, Wang, Z. Audrey, Wang, Jun, Mcdonald, Bryan, He, Peixiang, Yang, Qiyuan, Chen, Timothy, Varanasi, Siva Karthik, LaPorte, Michael, Mann, Thomas H., Chen, Dan, Hoffmann, Filipe, Ho, Josephine, Modliszewski, Jennifer, Williams, April, Liu, Yusha, Wang, Zhen, Liu, Jieyuan, Gao, Yiming, Hu, Zhiting, Cho, Ukrae H., Liu, Longwei, Wang, Yingxiao, Hargreaves, Diana C., Dotti, Gianpietro, Savoldo, Barbara, Thaxton, Jessica E., Milner, J. Justin, Kaech, Susan M., Wang, Wei

Issue&Volume: 2026-02-04

Abstract: CD8+ Tcells differentiate into diverse states that shape immune outcomes in cancer and chronic infection1,2,3,4. To define systematically the transcription factors (TFs) driving these states, we built a comprehensive atlas integrating transcriptional and epigenetic data across nine CD8+ Tcell states and inferred TF activity profiles. Our analysis catalogued TF activity fingerprints, uncovering regulatory mechanisms governing selective cell state differentiation. Leveraging this platform, we focused on two transcriptionally similar but functionally opposing states that are critical in tumour and viral contexts: terminally exhausted T(TEXterm) cells, which are dysfunctional5,6,7,8, and tissue-resident memory T(TRM) cells, which are protective9,10,11,12,13. Global TF community analysis revealed distinct biological pathways and TF-driven networks underlying protective versus dysfunctional states. Through in vivo CRISPR screening integrated with single-cell RNA sequencing (in vivo Perturb-seq) we delineated several TFs that selectively govern TEXterm cell differentiation. We also identified HIC1 and GFI1 as shared regulators of TEXterm and TRM cell differentiation and KLF6 as a unique regulator of TRM cells. We discovered new TEXterm-selective TFs, including ZSCAN20 and JDP2, with no previous known function in Tcells. Targeted deletion of these TFs enhanced tumour control and synergized with immune checkpoint blockade but did not interfere with TRM cell formation. Consistently, their depletion in human Tcells reduces the expression of inhibitory receptors and improves effector function. By decoupling exhaustion TEX-selective from protective TRM cell programmes, our platform enables more precise engineering of Tcell states, accelerating the rational design of more effective cellular immunotherapies.

DOI: 10.1038/s41586-025-09989-7

Source: https://www.nature.com/articles/s41586-025-09989-7