机构：[1]Institute for Immunology and School of Medicine, Tsinghua University, Beijing, China[2]Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA[3]Lung CancerCenter, West China Hospital, Sichuan University, Chengdu, Sichuan, China四川大学华西医院[4]Department of Systems Biology,The University of Texas MD Anderson CancerCenter, Houston, Texas, USA[5]Department of Melanoma Medical Oncology, The University of Texas MD Anderson CancerCenter, Houston, Texas, USA[6]Annoroad Gene Technology Co.Ltd.,Beijing, China[7]Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou MedicalUniversity, Xuzhou, Jiangsu, China[8]Faculty of Dentistry, The University of Hong Kong, Hong Kong SAR, China[9]Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military MedicalUniversity, Chongqing, China[10]Shanghai Immune Therapy Institute, Shanghai Jiao Tong University School of Medicine-Affiliated Renji Hospital, Shanghai, China
Forkhead box O transcriptional factors, especially FoxO1 and FoxO3a, play critical roles in physiologic and pathologic immune responses. However, the function of FoxO4, another main member of the FoxO family, in lymphoid cells is still poorly understood. Here, we showed that loss of FoxO4 in T cells augmented IFN-γ production of Th1 cells in vitro. Correspondingly, conditional deletion of FoxO4 in CD4+ T cells enhanced T cell-specific responses to Listeria monocytogenes infection in vivo. Genome-wide occupancy and transcriptomic analyses identified Dkk3 (encoding the Dickkopf-3 protein) as a direct transcriptional target of FoxO4. Consistent with the FoxO4-DKK3 relationship, recombinant DKK3 protein restored normal levels of IFN-γ production in FoxO4-deficient Th1 cells through the downregulation of lymphoid enhancer-binding factor 1 (Lef1) expression. Together, our data suggest a potential FoxO4/DKK3 axis in Th1 cell differentiation, providing what we believe to be an important insight and supplement for FoxO family proteins in T lymphocyte biology and revealing a promising target for the treatment of immune-related diseases.
基金：
National Natural
Science Foundation of China (31821003, 31991170, 3191173,
and 92169000, to CD; 81601371, to XC); the Shanghai Science
and Technology Commission (21JC1404200, to CD); the Sichuan
Science and Technology Program (2019YFS0111, to JH);
and the NIH (R21Al127997, to SHC).
语种：
外文
PubmedID：
中科院(CAS)分区：
出版当年[2022]版：
大类|1 区医学
小类|1 区医学：研究与实验
最新[2023]版：
大类|1 区医学
小类|1 区医学：研究与实验
第一作者：
第一作者机构：[1]Institute for Immunology and School of Medicine, Tsinghua University, Beijing, China[2]Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
共同第一作者：
通讯作者：
通讯机构：[1]Institute for Immunology and School of Medicine, Tsinghua University, Beijing, China[2]Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA[10]Shanghai Immune Therapy Institute, Shanghai Jiao Tong University School of Medicine-Affiliated Renji Hospital, Shanghai, China[*1]Department of Immunology, The University of Texas MD Anderson Cancer Center, 7455 Fannin Street, Houston, Texas 77030, USA.[*2]Institute for Immunology, Tsinghua University, 30 Shuangqing Road, Beijing 100085, China
推荐引用方式(GB/T 7714)：
Chen Xiang,Hu Jia,Wang Yunfei,et al.The FoxO4/DKK3 axis represses IFN-γ expression by Th1 cells and limits antimicrobial immunity[J].The Journal of clinical investigation.2022,132(18):doi:10.1172/JCI147566.
APA：
Chen Xiang,Hu Jia,Wang Yunfei,Lee Younghee,Zhao Xiaohong...&Dong Chen.(2022).The FoxO4/DKK3 axis represses IFN-γ expression by Th1 cells and limits antimicrobial immunity.The Journal of clinical investigation,132,(18)
MLA：
Chen Xiang,et al."The FoxO4/DKK3 axis represses IFN-γ expression by Th1 cells and limits antimicrobial immunity".The Journal of clinical investigation 132..18(2022)
医学