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, Huang Alexander C, Papazian Emily, Liu Ying, Rajasekaran Karthik, Brody Robert M, Thaler Erica R, Basu Devraj, Diab Ahmed, Giles Josephine R, Wherry E John
Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania; Philadelphia, PA, USA.
Institute for Immunology and Immune Health, Perelman School of Medicine, University of Pennsylvania; Philadelphia, PA, USA.
bioRxiv. 2025 Aug 11:2025.08.08.669213. doi: 10.1101/2025.08.08.669213.
Persistent antigen stimulation promotes differentiation of exhausted CD8 T (T) cells. T cells are distinct from circulating memory T (T) cells but share many features with tissue-resident memory (T) cells established following infection resolution. CD8 T cells co-expressing residency- and exhaustion-associated molecules in chronic diseases often correlate with clinical outcomes. However, the relationship between these cells and conventional T or T cells remains unclear. Here, we show that chronic antigen stimulation drives development of tissue-resident T (TR-T) cells that are ontologically and functionally distinct from T cells generated after antigen clearance. TR-T phenotypically resembled T cells but were regulated by distinct transcriptional networks and were uniquely dependent on Tox for residency programming. Although T progenitor cells acquired residency features upon entering chronically infected tissues, they failed to generate conventional T cells after antigen withdrawal. Conversely, T cells were able to differentiate into T cells during chronic antigen stimulation. Deriving cell-state specific transcriptional signatures revealed a selective association of TR-T cells with patient responses to immune checkpoint blockade, and only TR-T but not T cells responded to PD-1 pathway inhibition in vivo. These data suggest that TR-T and T cells are developmentally distinct cell types that share a tissue-residency program but have distinct roles in disease control.
持续的抗原刺激促进耗竭性CD8 T（T）细胞的分化。T细胞与循环记忆性T（T）细胞不同，但与感染消退后建立的组织驻留记忆性（T）细胞有许多共同特征。在慢性疾病中，共表达驻留和耗竭相关分子的CD8 T细胞常与临床结果相关。然而，这些细胞与传统T细胞或T细胞之间的关系仍不清楚。在这里，我们表明慢性抗原刺激驱动组织驻留性T（TR-T）细胞的发育，这些细胞在本体和功能上与抗原清除后产生的T细胞不同。TR-T在表型上类似于T细胞，但受不同的转录网络调控，并且在驻留编程方面独特地依赖于Tox。尽管T祖细胞在进入慢性感染组织时获得了驻留特征，但在抗原撤离后它们未能产生传统T细胞。相反，在慢性抗原刺激期间，T细胞能够分化为T细胞。推导细胞状态特异性转录特征揭示了TR-T细胞与患者对免疫检查点阻断反应的选择性关联，并且只有TR-T细胞而非T细胞在体内对PD-1途径抑制有反应。这些数据表明，TR-T细胞和T细胞是发育上不同的细胞类型，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。
