宾夕法尼亚大学E. John Wherry课题组的一项最新研究揭示了组织常驻耗竭和记忆性CD8⁺ T细胞在疾病中具有不同的个体发生、功能和作用。2025年12月29日出版的《自然—免疫学》发表了这项成果。

在这里，该研究组发现慢性抗原刺激驱动组织驻留TEX （TR-TEX）细胞的发育，这与抗原清除后产生的TRM细胞不同。TR-TEX和TRM细胞受不同的转录网络调控，只有TR-TEX细胞依赖于驻留编程。而TEX细胞（包括TR-TEX）在脱抗原后不能产生TRM细胞，而TRM细胞在慢性抗原暴露后分化为TEX细胞。细胞状态特异性转录特征揭示了TR-TEX细胞与患者免疫检查点阻断反应的选择性关联，并且在体内只有TR-TEX细胞而不是TRM细胞对PD-1通路抑制有反应。这些数据表明，TR-TEX和TRM细胞是发育不同的细胞状态，它们共享一个组织驻留程序，但在疾病控制中具有不同的作用。

据悉，慢性疾病中CD8⁺ T细胞共表达驻留和衰竭分子的存在通常与临床结果相关；然而，这些细胞与传统的组织驻留记忆（TRM）细胞或耗尽的CD8⁺ T （TEX）细胞之间的关系尚不清楚。

附：英文原文

Title: Tissue-resident exhausted and memory CD8+ T cells have distinct ontogeny, function and role in disease

Author: Park, Simone L., Painter, Mark M., Manne, Sasikanth, Alcalde, Victor, McLaughlin, Maura, Sullivan, Matthew A., Mathew, Divij, Torres, Leonel, Huang, Yinghui J., Reeg, David B., Douek, Naomi R., Campos, Trenton, Klapholz, Max, Cardenas, Maria A., Fang, Victoria, Ngiow, Shin Foong, KC, Wumesh, Goel, Rishi R., Baxter, Amy E., Wu, Jennifer E., Tan, Melody, Berry, Corbett T., Ellebrecht, Christoph T., Alexander, Huang C., Papazian, Emily, Liu, Ying, Rajasekaran, Karthik, Brody, Robert M., Thaler, Erica R., Basu, Devraj, Diab, Ahmed, Giles, Josephine R., Wherry, E. John

Issue&Volume: 2025-12-29

Abstract: The presence of CD8+ T cells coexpressing residency and exhaustion molecules in chronic diseases often correlate with clinical outcomes; however, the relationship between these cells and conventional tissue-resident memory (TRM) cells or exhausted CD8+ T (TEX) cells is unclear. Here we show that chronic antigen stimulation drives development of tissue-resident TEX (TR-TEX) cells that are distinct from TRM cells generated after antigen clearance. TR-TEX and TRM cells are regulated by different transcriptional networks with only TR-TEX cells being Tox-dependent for residency programming. While TEX cells (including TR-TEX) are unable to generate TRM cells after antigen withdrawal, TRM cells differentiate into TEX cells upon chronic antigen exposure. Cell-state-specific transcriptional signatures reveal a selective association of TR-TEX cells with patient responses to immune checkpoint blockade, and only TR-TEX but not TRM cells responded to PD-1 pathway inhibition in vivo. These data suggest that TR-TEX and TRM cells are developmentally divergent cell states that share a tissue-residency program but have distinct roles in disease control.

DOI: 10.1038/s41590-025-02352-y

Source: https://www.nature.com/articles/s41590-025-02352-y