Glycogen synthase kinase 3 controls T-cell exhaustion by regulating NFAT activation

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外文摘要：Cellular immunity mediated by CD8+T cells plays an indispensable role in bacterial and viral clearance and cancers.However,persistent antigen stimulation of CD8+T cells leads to an exhausted or dysfunctional cellular state characterized by the loss of effector function and high expression of inhibitory receptors during chronic viral infection and in tumors.Numerous studies have shown that glycogen synthase kinase 3(GSK3)controls the function and development of immune cells,but whether GSK3 affects CD8+T cells is not clearly elucidated.Here,we demonstrate that mice with deletion of Gsk3α and Gsk3β in activated CD8+T cells(DKO)exhibited decreased CTL differentiation and effector function during acute and chronic viral infection.In addition,DKO mice failed to control tumor growth due to the upregulated expression of inhibitory receptors and augmented T-cell exhaustion in tumor-infiltrating CD8+T cells.Strikingly,anti-PD-1 immunotherapy substantially restored tumor rejection in DKO mice.Mechanistically,GSK3 regulates T-cell exhaustion by suppressing TCR-induced nuclear import of NFAT,thereby in turn dampening NFAT-mediated exhaustion-related gene expression,including TOX/TOX2 and PD-1.Thus,we uncovered the molecular mechanisms underlying GSK3 regulation of CTL differentiation and T-cell exhaustion in anti-tumor immune responses.

外文关键词：

GSK3T-cell exhaustionViral infectionAnti-tumor immunityInhibitory receptors

作者：

Yubing Fu、Jinjia Wang、Chenfeng Liu、Kunyu Liao、Xianjun Gao、Ronghan Tang、Binbin Fan、Yazhen Hong、Nengming Xiao、Changchun Xiao、Wen-Hsien Liu

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作者单位：

State Key Laboratory of Cellular Stress Biology,School of Life Sciences,Faculty of Medicine and Life Science,Xiamen University,Xiamen 361102 Fujian,China

Department of Cell Biology,School of Life Science,Anhui Medical University,Hefei 230031 Anhui,China

Sanofi Institute for Biomedical Research,Suzhou,Jiangsu 215123,China

基金：

National Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of China1000 Young Talents Program of China(NX)Fundamental Research Funds for the Central Universities of China-Xiamen University

项目编号：

3177095381830047819611380083207087720720170064

出版年：

2023

DOI：

10.1038/s41423-023-01075-0

中国免疫学杂志(英文版)

中国免疫学会

中国免疫学杂志(英文版)

CSTPCDCSCDSCI

影响因子：0.731

ISSN：1672-7681

年,卷(期)：2023.20(10)

参考文献量41