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

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 

机构地区：[1]State Key Laboratory of Cellular Stress Biology,School of Life Sciences,Faculty of Medicine and Life Science,Xiamen University,Xiamen,361102,Fujian,China [2]Department of Cell Biology,School of Life Science,Anhui Medical University,Hefei,230031,Anhui,China [3]Sanof institute for Biomedical Research,Suzhou,Jiangsu 215123 China.

出　　处：《Cellular & Molecular Immunology》2023年第10期1127-1139,共13页中国免疫学杂志（英文版）

基　　金：supported by the National Natural Science Foundation of China(31770953,81830047,and 81961138008 to CX and 32070877 to W-HL),1000 Young Talents Program of China(NX);the Fundamental Research Funds for the Central Universities of China-Xiamen University(20720170064 to CX).

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 Gsk3αand Gsk3βin 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.

关 键 词：GSK3 T-cell exhaustion Viral infection Anti-tumor immunity Inhibitory receptors 

分 类 号：R392[医药卫生—免疫学]