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

IF 25.5 1区 医学 Q1 IMMUNOLOGY
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
{"title":"The costimulatory molecule ICOS limits memory-like properties and function of exhausted PD-1+CD8+ T cells","authors":"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","doi":"10.1016/j.immuni.2025.06.001","DOIUrl":null,"url":null,"abstract":"During persistent antigen stimulation, CD8<sup>+</sup> T cell responses are maintained by progenitor exhausted CD8<sup>+</sup> 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<sup>+</sup>CD8<sup>+</sup> T cells is not clear. During chronic infection, intrinsic ICOS deficiency increased number and quality of virus-specific CD8<sup>+</sup> 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<sup>+</sup>CD8<sup>+</sup> 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<sup>+</sup> T cell responses and tumor control by PD-1 blockade. Overall, we show that sustained ICOS costimulation limits CD8<sup>+</sup> T cell responses during chronic antigen exposure.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"21 1","pages":""},"PeriodicalIF":25.5000,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Immunity","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.immuni.2025.06.001","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"IMMUNOLOGY","Score":null,"Total":0}
引用次数: 0

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.

Abstract Image

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
在持续的抗原刺激过程中,CD8+ T细胞反应由耗尽的祖细胞(Tpex)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,在小鼠肝细胞癌模型中,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。总的来说,我们发现持续的ICOS共刺激限制了慢性抗原暴露期间CD8+ T细胞的反应。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
Immunity
Immunity 医学-免疫学
CiteScore
49.40
自引率
2.20%
发文量
205
审稿时长
6 months
期刊介绍: Immunity is a publication that focuses on publishing significant advancements in research related to immunology. We encourage the submission of studies that offer groundbreaking immunological discoveries, whether at the molecular, cellular, or whole organism level. Topics of interest encompass a wide range, such as cancer, infectious diseases, neuroimmunology, autoimmune diseases, allergies, mucosal immunity, metabolic diseases, and homeostasis.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:604180095
Book学术官方微信