澳大利亚墨尔本大学Axel Kallies研究组提出了转录调节因子SATB1限制CD8⁺ T细胞群扩增和慢性感染和癌症的效应分化。相关论文于2025年10月27日发表于国际顶尖学术期刊《自然—免疫学》杂志上。

在这里，课题组发现染色质组织者和转录调节剂SATB1是耗尽CD8⁺ T细胞分化的主要调节剂。SATB1在TPEX细胞中特异性表达，它在保留CD8⁺ T细胞功能的同时限制了群体扩增和效应分化。在慢性感染中，SATB1下调是TPEX细胞向效应细胞分化所必需的，在急性病毒感染中，SATB1下调有助于协调效应和记忆分化。SATB1的DNA结合调节了依赖和独立于染色质可及性的基因表达。最后，SATB1限制抗肿瘤CD8⁺和嵌合抗原受体T细胞免疫。总的来说，他们的结果确定SATB1是感染和癌症中CD8⁺ T细胞前体命运和效应分化的中心调节因子。

据悉，CD8⁺ T细胞是抗病毒和抗肿瘤免疫的主要介质。然而，在慢性感染和癌症等持续性抗原刺激过程中，它们分化为衰竭的T细胞，表现出功能受损。衰竭T细胞（TPEX）的前体表现出干细胞样特性，包括高增殖、自我更新和发育潜力，并负责CD8⁺ T细胞对持久性抗原的长期反应。

附：英文原文

Title: Transcriptional regulator SATB1 limits CD8+ T cell population expansion and effector differentiation in chronic infection and cancer

Author: Heyden, Leonie, Rausch, Lisa, Shannon, Michael H., Dryburgh, Lachlan, Moreira, Marcela L., Frolov, Aleksej, Scheffler, Christina M., van Elsas, Marit J., Tong, Junming, Hidajat, Olivia, Wijesinghe, Sharanya K. M., Li, Sining, Horvatic, Helena, Huynh-Anh, Nhat Truong, Gago da Graa, Catarina, Tsui, Carlson, Khne, Maren, Sommer, Daniel, Wunderlich, F. Thomas, von Scheidt, Bianca, Park, Simone L., Mackay, Laura K., Utzschneider, Daniel T., Schrder, Jan, Turner, Stephen J., Darcy, Phillip K., Beyer, Marc D., Abdullah, Zeinab, Kallies, Axel

Issue&Volume: 2025-10-27

Abstract: CD8+ T cells are major mediators of antiviral and antitumor immunity. During persistent antigen stimulation as in chronic infection and cancer, however, they differentiate into exhausted T cells that display impaired functionality. Precursors of exhausted T (TPEX) cells exhibit stem-like properties, including high proliferative, self-renewal and developmental potential, and are responsible for long-term CD8+ T cell responses against persistent antigens. Here we identify the chromatin organizer and transcriptional regulator SATB1 as a major regulator of exhausted CD8+ T cell differentiation. SATB1 was specifically expressed in TPEX cells where it limited population expansion and effector differentiation while preserving functionality of CD8+ T cells. SATB1 downregulation was required for TPEX cell-to-effector cell differentiation in chronic infection and contributed to coordinated effector and memory differentiation in acute viral infection. DNA binding of SATB1 regulated gene expression both dependent and independent of chromatin accessibility. Finally, SATB1 limited antitumor CD8+ and chimeric antigen receptor T cell immunity. Overall, our results identify SATB1 as a central regulator of precursor fate and effector differentiation of CD8+ T cells both in infection and in cancer.

DOI: 10.1038/s41590-025-02316-2

Source: https://www.nature.com/articles/s41590-025-02316-2