近日，美国马克和詹妮弗·利普舒尔茨精密免疫学研究所教授Alice O. Kamphorst及其课题组的研究显示，共刺激分子ICOS限制了耗竭的PD-1⁺CD8⁺ T细胞的记忆样特性和功能。相关论文于2025年7月7日发表在《免疫学》杂志上。

总的来说，研究小组发现持续的ICOS共刺激限制了慢性抗原暴露期间CD8⁺ T细胞的反应。

据悉，在持续的抗原刺激过程中，CD8⁺ T细胞反应由祖细胞衰竭的CD8⁺ T （Tpex）细胞维持。Tpex细胞对抑制受体程序性细胞死亡-1 （PD-1）的阻断有反应，对其分化的调节对免疫治疗至关重要。Tpex细胞高度表达诱导共刺激因子（ICOS），但ICOS如何调节PD-1+CD8⁺ T细胞尚不清楚。在慢性感染期间，内在的ICOS缺乏增加了病毒特异性CD8⁺ T细胞的数量和质量。ICOS的缺失增强了转录因子叉头盒O1 （FoxO1）的活性和Tpex细胞的记忆样特征。缺乏ICOS的Tpex细胞可以产生效应样细胞，提高存活率和细胞因子的产生。ICOSL阻断扩大了效应样PD-1⁺CD8⁺ T细胞，降低了病毒载量，提高了对PD-1阻断的应答。同样，在肝细胞癌的单主题模型中，ICOS抑制增强了肿瘤特异性CD8⁺ T细胞反应和PD-1阻断对肿瘤的控制。

附：英文原文

Title: The costimulatory molecule ICOS limits memory-like properties and function of exhausted PD-1+CD8+ T cells

Author: Etienne Humblin, Isabel Korpas, Nataliya Prokhnevska, Abishek Vaidya, Dan Filipescu, Jiahua Lu, Verena van der Heide, Carlos Alberto de Carvalho Fraga, Tesia Bobrowski, Adam Marks, Matthew D. Park, Helder I. Nakaya, Emily Bernstein, Brian D. Brown, Amaia Lujambio, David Dominguez-Sola, Brad R. Rosenberg, Alice O. Kamphorst

Issue&Volume: 2025-07-07

Abstract: During persistent antigen stimulation, CD8+ T cell responses are maintained by progenitor exhausted CD8+ T (Tpex) cells. Tpex cells respond to blockade of the inhibitory receptor programmed cell death-1 (PD-1), and regulation of their differentiation is critical for immunotherapies. Tpex cells highly express inducible costimulator (ICOS), but how ICOS modulates PD-1+CD8+ T cells is not clear. During chronic infection, intrinsic ICOS deficiency increased number and quality of virus-specific CD8+ T cells. Loss of ICOS potentiated activity of the transcription factor forkhead box O1 (FoxO1) and memory-like features of Tpex cells. ICOS-deficient Tpex cells were poised to generate effecor-like cells with improved survival and cytokine production. ICOS-ligand (ICOSL) blockade expanded effector-like PD-1+CD8+ T cells, reduced viral load, and improved response to PD-1 blockade. Similarly, in a mouse model of hepatocellular carcinoma, ICOS inhibition enhanced tumor-specific CD8+ T cell responses and tumor control by PD-1 blockade. Overall, we show that sustained ICOS costimulation limits CD8+ T cell responses during chronic antigen exposure.

DOI: 10.1016/j.immuni.2025.06.001

Source: https://www.cell.com/immunity/abstract/S1074-7613(25)00248-1