The FoxO4/DKK3 axis represses IFN-γ expression by Th1 cells and limits antimicrobial immunity

Research ArticleImmunology Open Access | 10.1172/JCI147566

Xiang Chen,1,2 Jia Hu,3,4 Yunfei Wang,5 Younghee Lee,2 Xiaohong Zhao,1 Huiping Lu,1,6 Gengzhen Zhu,1 Hui Wang,7 Yu Jiang,1 Fan Liu,8 Yongzhen Chen,1 Byung-Seok Kim,2 Qinghua Zhou,3 Xindong Liu,9 Xiaohu Wang,1 Seon Hee Chang,2 and Chen Dong1,10

1Institute for Immunology and School of Medicine, Tsinghua University, Beijing, China.

2Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

3Lung Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China.

4Department of Systems Biology, and

5Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

6Annoroad Gene Technology Co. Ltd., Beijing, China.

7Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu, China.

8Faculty of Dentistry, The University of Hong Kong, Hong Kong SAR, China.

9Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, China.

10Shanghai Immune Therapy Institute, Shanghai Jiao Tong University School of Medicine-Affiliated Renji Hospital, Shanghai, China.

Address correspondence to: Seon Hee Chang, Department of Immunology, The University of Texas MD Anderson Cancer Center, 7455 Fannin Street, Houston, Texas 77030, USA. Phone: 713.563.3302; Email: shchang@mdanderson.org. Or to: Chen Dong, Institute for Immunology, Tsinghua University, 30 Shuangqing Road, Beijing 100085, China. Phone: 86.10.6279.8973; Email: chendong@tsinghua.edu.cn.

Authorship note: XC and JH contributed equally to this work. SHC and CD contributed equally to this work and are co–senior authors.

Find articles by Chen, X. in: JCI | PubMed | Google Scholar

1Institute for Immunology and School of Medicine, Tsinghua University, Beijing, China.

2Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

3Lung Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China.

4Department of Systems Biology, and

5Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

6Annoroad Gene Technology Co. Ltd., Beijing, China.

7Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu, China.

8Faculty of Dentistry, The University of Hong Kong, Hong Kong SAR, China.

9Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, China.

10Shanghai Immune Therapy Institute, Shanghai Jiao Tong University School of Medicine-Affiliated Renji Hospital, Shanghai, China.

Address correspondence to: Seon Hee Chang, Department of Immunology, The University of Texas MD Anderson Cancer Center, 7455 Fannin Street, Houston, Texas 77030, USA. Phone: 713.563.3302; Email: shchang@mdanderson.org. Or to: Chen Dong, Institute for Immunology, Tsinghua University, 30 Shuangqing Road, Beijing 100085, China. Phone: 86.10.6279.8973; Email: chendong@tsinghua.edu.cn.

Authorship note: XC and JH contributed equally to this work. SHC and CD contributed equally to this work and are co–senior authors.

Find articles by Hu, J. in: JCI | PubMed | Google Scholar

1Institute for Immunology and School of Medicine, Tsinghua University, Beijing, China.

2Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

3Lung Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China.

4Department of Systems Biology, and

5Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

6Annoroad Gene Technology Co. Ltd., Beijing, China.

7Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu, China.

8Faculty of Dentistry, The University of Hong Kong, Hong Kong SAR, China.

9Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, China.

10Shanghai Immune Therapy Institute, Shanghai Jiao Tong University School of Medicine-Affiliated Renji Hospital, Shanghai, China.

Address correspondence to: Seon Hee Chang, Department of Immunology, The University of Texas MD Anderson Cancer Center, 7455 Fannin Street, Houston, Texas 77030, USA. Phone: 713.563.3302; Email: shchang@mdanderson.org. Or to: Chen Dong, Institute for Immunology, Tsinghua University, 30 Shuangqing Road, Beijing 100085, China. Phone: 86.10.6279.8973; Email: chendong@tsinghua.edu.cn.

Authorship note: XC and JH contributed equally to this work. SHC and CD contributed equally to this work and are co–senior authors.

Find articles by Wang, Y. in: JCI | PubMed | Google Scholar |

1Institute for Immunology and School of Medicine, Tsinghua University, Beijing, China.

2Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

3Lung Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China.

4Department of Systems Biology, and

5Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

6Annoroad Gene Technology Co. Ltd., Beijing, China.

7Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu, China.

8Faculty of Dentistry, The University of Hong Kong, Hong Kong SAR, China.

9Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, China.

10Shanghai Immune Therapy Institute, Shanghai Jiao Tong University School of Medicine-Affiliated Renji Hospital, Shanghai, China.

Address correspondence to: Seon Hee Chang, Department of Immunology, The University of Texas MD Anderson Cancer Center, 7455 Fannin Street, Houston, Texas 77030, USA. Phone: 713.563.3302; Email: shchang@mdanderson.org. Or to: Chen Dong, Institute for Immunology, Tsinghua University, 30 Shuangqing Road, Beijing 100085, China. Phone: 86.10.6279.8973; Email: chendong@tsinghua.edu.cn.

Authorship note: XC and JH contributed equally to this work. SHC and CD contributed equally to this work and are co–senior authors.

Find articles by Lee, Y. in: JCI | PubMed | Google Scholar

1Institute for Immunology and School of Medicine, Tsinghua University, Beijing, China.

2Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

3Lung Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China.

4Department of Systems Biology, and

5Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

6Annoroad Gene Technology Co. Ltd., Beijing, China.

7Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu, China.

8Faculty of Dentistry, The University of Hong Kong, Hong Kong SAR, China.

9Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, China.

10Shanghai Immune Therapy Institute, Shanghai Jiao Tong University School of Medicine-Affiliated Renji Hospital, Shanghai, China.

Address correspondence to: Seon Hee Chang, Department of Immunology, The University of Texas MD Anderson Cancer Center, 7455 Fannin Street, Houston, Texas 77030, USA. Phone: 713.563.3302; Email: shchang@mdanderson.org. Or to: Chen Dong, Institute for Immunology, Tsinghua University, 30 Shuangqing Road, Beijing 100085, China. Phone: 86.10.6279.8973; Email: chendong@tsinghua.edu.cn.

Authorship note: XC and JH contributed equally to this work. SHC and CD contributed equally to this work and are co–senior authors.

Find articles by Zhao, X. in: JCI | PubMed | Google Scholar

1Institute for Immunology and School of Medicine, Tsinghua University, Beijing, China.

2Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

3Lung Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China.

4Department of Systems Biology, and

5Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

6Annoroad Gene Technology Co. Ltd., Beijing, China.

7Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu, China.

8Faculty of Dentistry, The University of Hong Kong, Hong Kong SAR, China.

9Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, China.

10Shanghai Immune Therapy Institute, Shanghai Jiao Tong University School of Medicine-Affiliated Renji Hospital, Shanghai, China.

Address correspondence to: Seon Hee Chang, Department of Immunology, The University of Texas MD Anderson Cancer Center, 7455 Fannin Street, Houston, Texas 77030, USA. Phone: 713.563.3302; Email: shchang@mdanderson.org. Or to: Chen Dong, Institute for Immunology, Tsinghua University, 30 Shuangqing Road, Beijing 100085, China. Phone: 86.10.6279.8973; Email: chendong@tsinghua.edu.cn.

Authorship note: XC and JH contributed equally to this work. SHC and CD contributed equally to this work and are co–senior authors.

Find articles by Lu, H. in: JCI | PubMed | Google Scholar |

1Institute for Immunology and School of Medicine, Tsinghua University, Beijing, China.

2Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

3Lung Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China.

4Department of Systems Biology, and

5Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

6Annoroad Gene Technology Co. Ltd., Beijing, China.

7Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu, China.

8Faculty of Dentistry, The University of Hong Kong, Hong Kong SAR, China.

9Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, China.

10Shanghai Immune Therapy Institute, Shanghai Jiao Tong University School of Medicine-Affiliated Renji Hospital, Shanghai, China.

Address correspondence to: Seon Hee Chang, Department of Immunology, The University of Texas MD Anderson Cancer Center, 7455 Fannin Street, Houston, Texas 77030, USA. Phone: 713.563.3302; Email: shchang@mdanderson.org. Or to: Chen Dong, Institute for Immunology, Tsinghua University, 30 Shuangqing Road, Beijing 100085, China. Phone: 86.10.6279.8973; Email: chendong@tsinghua.edu.cn.

Authorship note: XC and JH contributed equally to this work. SHC and CD contributed equally to this work and are co–senior authors.

Find articles by Zhu, G. in: JCI | PubMed | Google Scholar

1Institute for Immunology and School of Medicine, Tsinghua University, Beijing, China.

2Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

3Lung Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China.

4Department of Systems Biology, and

5Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

6Annoroad Gene Technology Co. Ltd., Beijing, China.

7Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu, China.

8Faculty of Dentistry, The University of Hong Kong, Hong Kong SAR, China.

9Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, China.

10Shanghai Immune Therapy Institute, Shanghai Jiao Tong University School of Medicine-Affiliated Renji Hospital, Shanghai, China.

Address correspondence to: Seon Hee Chang, Department of Immunology, The University of Texas MD Anderson Cancer Center, 7455 Fannin Street, Houston, Texas 77030, USA. Phone: 713.563.3302; Email: shchang@mdanderson.org. Or to: Chen Dong, Institute for Immunology, Tsinghua University, 30 Shuangqing Road, Beijing 100085, China. Phone: 86.10.6279.8973; Email: chendong@tsinghua.edu.cn.

Authorship note: XC and JH contributed equally to this work. SHC and CD contributed equally to this work and are co–senior authors.

Find articles by Wang, H. in: JCI | PubMed | Google Scholar

1Institute for Immunology and School of Medicine, Tsinghua University, Beijing, China.

2Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

3Lung Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China.

4Department of Systems Biology, and

5Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

6Annoroad Gene Technology Co. Ltd., Beijing, China.

7Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu, China.

8Faculty of Dentistry, The University of Hong Kong, Hong Kong SAR, China.

9Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, China.

10Shanghai Immune Therapy Institute, Shanghai Jiao Tong University School of Medicine-Affiliated Renji Hospital, Shanghai, China.

Address correspondence to: Seon Hee Chang, Department of Immunology, The University of Texas MD Anderson Cancer Center, 7455 Fannin Street, Houston, Texas 77030, USA. Phone: 713.563.3302; Email: shchang@mdanderson.org. Or to: Chen Dong, Institute for Immunology, Tsinghua University, 30 Shuangqing Road, Beijing 100085, China. Phone: 86.10.6279.8973; Email: chendong@tsinghua.edu.cn.

Authorship note: XC and JH contributed equally to this work. SHC and CD contributed equally to this work and are co–senior authors.

Find articles by Jiang, Y. in: JCI | PubMed | Google Scholar

1Institute for Immunology and School of Medicine, Tsinghua University, Beijing, China.

2Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

3Lung Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China.

4Department of Systems Biology, and

5Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

6Annoroad Gene Technology Co. Ltd., Beijing, China.

7Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu, China.

8Faculty of Dentistry, The University of Hong Kong, Hong Kong SAR, China.

9Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, China.

10Shanghai Immune Therapy Institute, Shanghai Jiao Tong University School of Medicine-Affiliated Renji Hospital, Shanghai, China.

Address correspondence to: Seon Hee Chang, Department of Immunology, The University of Texas MD Anderson Cancer Center, 7455 Fannin Street, Houston, Texas 77030, USA. Phone: 713.563.3302; Email: shchang@mdanderson.org. Or to: Chen Dong, Institute for Immunology, Tsinghua University, 30 Shuangqing Road, Beijing 100085, China. Phone: 86.10.6279.8973; Email: chendong@tsinghua.edu.cn.

Authorship note: XC and JH contributed equally to this work. SHC and CD contributed equally to this work and are co–senior authors.

Find articles by Liu, F. in: JCI | PubMed | Google Scholar

1Institute for Immunology and School of Medicine, Tsinghua University, Beijing, China.

2Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

3Lung Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China.

4Department of Systems Biology, and

5Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

6Annoroad Gene Technology Co. Ltd., Beijing, China.

7Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu, China.

8Faculty of Dentistry, The University of Hong Kong, Hong Kong SAR, China.

9Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, China.

10Shanghai Immune Therapy Institute, Shanghai Jiao Tong University School of Medicine-Affiliated Renji Hospital, Shanghai, China.

Address correspondence to: Seon Hee Chang, Department of Immunology, The University of Texas MD Anderson Cancer Center, 7455 Fannin Street, Houston, Texas 77030, USA. Phone: 713.563.3302; Email: shchang@mdanderson.org. Or to: Chen Dong, Institute for Immunology, Tsinghua University, 30 Shuangqing Road, Beijing 100085, China. Phone: 86.10.6279.8973; Email: chendong@tsinghua.edu.cn.

Authorship note: XC and JH contributed equally to this work. SHC and CD contributed equally to this work and are co–senior authors.

Find articles by Chen, Y. in: JCI | PubMed | Google Scholar

1Institute for Immunology and School of Medicine, Tsinghua University, Beijing, China.

2Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

3Lung Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China.

4Department of Systems Biology, and

5Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

6Annoroad Gene Technology Co. Ltd., Beijing, China.

7Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu, China.

8Faculty of Dentistry, The University of Hong Kong, Hong Kong SAR, China.

9Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, China.

10Shanghai Immune Therapy Institute, Shanghai Jiao Tong University School of Medicine-Affiliated Renji Hospital, Shanghai, China.

Address correspondence to: Seon Hee Chang, Department of Immunology, The University of Texas MD Anderson Cancer Center, 7455 Fannin Street, Houston, Texas 77030, USA. Phone: 713.563.3302; Email: shchang@mdanderson.org. Or to: Chen Dong, Institute for Immunology, Tsinghua University, 30 Shuangqing Road, Beijing 100085, China. Phone: 86.10.6279.8973; Email: chendong@tsinghua.edu.cn.

Authorship note: XC and JH contributed equally to this work. SHC and CD contributed equally to this work and are co–senior authors.

Find articles by Kim, B. in: JCI | PubMed | Google Scholar |

1Institute for Immunology and School of Medicine, Tsinghua University, Beijing, China.

2Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

3Lung Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China.

4Department of Systems Biology, and

5Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

6Annoroad Gene Technology Co. Ltd., Beijing, China.

7Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu, China.

8Faculty of Dentistry, The University of Hong Kong, Hong Kong SAR, China.

9Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, China.

10Shanghai Immune Therapy Institute, Shanghai Jiao Tong University School of Medicine-Affiliated Renji Hospital, Shanghai, China.

Address correspondence to: Seon Hee Chang, Department of Immunology, The University of Texas MD Anderson Cancer Center, 7455 Fannin Street, Houston, Texas 77030, USA. Phone: 713.563.3302; Email: shchang@mdanderson.org. Or to: Chen Dong, Institute for Immunology, Tsinghua University, 30 Shuangqing Road, Beijing 100085, China. Phone: 86.10.6279.8973; Email: chendong@tsinghua.edu.cn.

Authorship note: XC and JH contributed equally to this work. SHC and CD contributed equally to this work and are co–senior authors.

Find articles by Zhou, Q. in: JCI | PubMed | Google Scholar

1Institute for Immunology and School of Medicine, Tsinghua University, Beijing, China.

2Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

3Lung Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China.

4Department of Systems Biology, and

5Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

6Annoroad Gene Technology Co. Ltd., Beijing, China.

7Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu, China.

8Faculty of Dentistry, The University of Hong Kong, Hong Kong SAR, China.

9Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, China.

10Shanghai Immune Therapy Institute, Shanghai Jiao Tong University School of Medicine-Affiliated Renji Hospital, Shanghai, China.

Address correspondence to: Seon Hee Chang, Department of Immunology, The University of Texas MD Anderson Cancer Center, 7455 Fannin Street, Houston, Texas 77030, USA. Phone: 713.563.3302; Email: shchang@mdanderson.org. Or to: Chen Dong, Institute for Immunology, Tsinghua University, 30 Shuangqing Road, Beijing 100085, China. Phone: 86.10.6279.8973; Email: chendong@tsinghua.edu.cn.

Authorship note: XC and JH contributed equally to this work. SHC and CD contributed equally to this work and are co–senior authors.

Find articles by Liu, X. in: JCI | PubMed | Google Scholar

1Institute for Immunology and School of Medicine, Tsinghua University, Beijing, China.

2Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

3Lung Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China.

4Department of Systems Biology, and

5Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

6Annoroad Gene Technology Co. Ltd., Beijing, China.

7Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu, China.

8Faculty of Dentistry, The University of Hong Kong, Hong Kong SAR, China.

9Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, China.

10Shanghai Immune Therapy Institute, Shanghai Jiao Tong University School of Medicine-Affiliated Renji Hospital, Shanghai, China.

Address correspondence to: Seon Hee Chang, Department of Immunology, The University of Texas MD Anderson Cancer Center, 7455 Fannin Street, Houston, Texas 77030, USA. Phone: 713.563.3302; Email: shchang@mdanderson.org. Or to: Chen Dong, Institute for Immunology, Tsinghua University, 30 Shuangqing Road, Beijing 100085, China. Phone: 86.10.6279.8973; Email: chendong@tsinghua.edu.cn.

Authorship note: XC and JH contributed equally to this work. SHC and CD contributed equally to this work and are co–senior authors.

Find articles by Wang, X. in: JCI | PubMed | Google Scholar

1Institute for Immunology and School of Medicine, Tsinghua University, Beijing, China.

2Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

3Lung Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China.

4Department of Systems Biology, and

5Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

6Annoroad Gene Technology Co. Ltd., Beijing, China.

7Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu, China.

8Faculty of Dentistry, The University of Hong Kong, Hong Kong SAR, China.

9Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, China.

10Shanghai Immune Therapy Institute, Shanghai Jiao Tong University School of Medicine-Affiliated Renji Hospital, Shanghai, China.

Address correspondence to: Seon Hee Chang, Department of Immunology, The University of Texas MD Anderson Cancer Center, 7455 Fannin Street, Houston, Texas 77030, USA. Phone: 713.563.3302; Email: shchang@mdanderson.org. Or to: Chen Dong, Institute for Immunology, Tsinghua University, 30 Shuangqing Road, Beijing 100085, China. Phone: 86.10.6279.8973; Email: chendong@tsinghua.edu.cn.

Authorship note: XC and JH contributed equally to this work. SHC and CD contributed equally to this work and are co–senior authors.

Find articles by Chang, S. in: JCI | PubMed | Google Scholar |

1Institute for Immunology and School of Medicine, Tsinghua University, Beijing, China.

2Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

3Lung Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China.

4Department of Systems Biology, and

5Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

6Annoroad Gene Technology Co. Ltd., Beijing, China.

7Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu, China.

8Faculty of Dentistry, The University of Hong Kong, Hong Kong SAR, China.

9Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, China.

10Shanghai Immune Therapy Institute, Shanghai Jiao Tong University School of Medicine-Affiliated Renji Hospital, Shanghai, China.

Address correspondence to: Seon Hee Chang, Department of Immunology, The University of Texas MD Anderson Cancer Center, 7455 Fannin Street, Houston, Texas 77030, USA. Phone: 713.563.3302; Email: shchang@mdanderson.org. Or to: Chen Dong, Institute for Immunology, Tsinghua University, 30 Shuangqing Road, Beijing 100085, China. Phone: 86.10.6279.8973; Email: chendong@tsinghua.edu.cn.

Authorship note: XC and JH contributed equally to this work. SHC and CD contributed equally to this work and are co–senior authors.

Find articles by Dong, C. in: JCI | PubMed | Google Scholar |

Authorship note: XC and JH contributed equally to this work. SHC and CD contributed equally to this work and are co–senior authors.

Published September 15, 2022 - More info

Published in Volume 132, Issue 18 on September 15, 2022
J Clin Invest. 2022;132(18):e147566. https://doi.org/10.1172/JCI147566.
© 2022 Chen et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Published September 15, 2022 - Version history
Received: January 13, 2021; Accepted: July 21, 2022 View PDF Abstract

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.

Graphical Abstractgraphical abstract Introduction

CD4+ helper T cells are central regulators of adaptive immune responses. After encountering a specific antigen on antigen-presenting cells, CD4+ T cells undergo clonal expansion and differentiate into functionally distinct effector subsets, including at least T helper 1 (Th1), Th2, Th17, and T follicular helper (Tfh) cells, which orchestrate immune responses against diverse microbial pathogens. Among these, IFN-γ–producing Th1 cells specialize in activating cell-mediated immune responses against intracellular pathogens and viruses. The differentiation of CD4+ T cells into Th1 cells is determined by T-bet (encoded by Tbx21), the master regulator of the Th1 differentiation program (1). Initially, T-bet is induced in response to TCR stimulation and IFN-γ/STAT1 signaling (2, 3). T-bet functions, in part, to upregulate the expression of Il12rb (encoding IL-12Rβ), enabling developing Th1 cells to respond to IL-12 (4). As a result, a fully polarized Th1 phenotype is established by IL-12–induced STAT4 activation (5). Thus, the T-bet–STAT4 transcriptional regulatory network maintains stability of the Th1 differentiation program, ensuring CD4+ T cells receive proinflammatory signals as well as antigen stimulation to go fully committed into the Th1 cell lineage.

FoxO transcription factors belong to the family of forkhead proteins that are characterized by the presence of an approximately 100-residue forkhead DNA-binding domain. FoxO proteins function as transcriptional regulators and activate the transcription of downstream genes involved in a variety of biological processes including cellular metabolism, organ development, stress responses, and apoptosis (6, 7). In lymphoid cells, FoxO1 and FoxO3a have been shown to cooperatively regulate the generation of Foxp3+ Tregs from conventional T cells by binding to the promoter and the conserved CNS2 intronic enhancer region of the Foxp3 locus (8, 9). In addition, FoxO1 inhibits Th1 differentiation through direct binding to the Ifng gene promoter region (8). Conversely, FoxO3a drives pathogenic Th1 differentiation by inducing Eomes expression (10). In addition to Tregs and Th1 cells, FoxO transcription factors have also been reported to negatively regulate the generation of Tfh and Th17 cells. Mice with T cell–specific FoxO1 deletion accumulate a large population of Tfh cells, perhaps because FoxO1 binds to the Bcl6 gene locus and mediates its transcriptional repression (11). FoxO1 suppresses the Th17 program in vitro and in vivo by blocking RORγt binding to its target genes (12). In addition, FoxO4 has been shown to regulate insulin signaling and apoptosis (13), yet its role in lymphoid cell biology has not been well addressed.

The Dickkopf (DKK) family of glycoproteins (DKK1–4) are involved in modulating Wnt signaling pathways (14). As the best-characterized member of the DKK family, DKK1, a natural inhibitor of Wnt signaling, inhibits tumor growth and metastasis (15) and promotes Th2 differentiation (16). Moreover, DKK2 was reported to promote tumor immunity evasion through a Wnt-independent signaling pathway (17). In contrast to DKK1 and DKK2, the signaling by DKK3 is still unclear, with reports showing no effect, promotion, or inhibition of the Wnt signaling pathway (1820). Similarly, the functional roles of DKK3 in immunity are unclear, with conflicting studies reporting its immunomodulatory or immunostimulatory functions (21, 22), suggesting that DKK3 may regulate immunity through a different mechanism.

In this study, we investigated the role of FoxO4 in T cells and found that loss of FoxO4 enhanced IFN-γ production and the effector function of Th1 cells in vitro and in vivo. Mechanistically, we identified Dkk3 as a direct transcriptional target of FoxO4, which inhibits IFN-γ production through the downregulation of lymphoid enhancer–binding factor 1 (Lef1) expression. Thus, our work identifies a critical axis of FoxO4/DKK3/LEF-1 in regulating Th1 cell differentiation, which is different from other FoxO family members.

Results

FoxO4 is dispensable in T cell homeostasis. To study the role of FoxO4 in T lymphocytes, we first examined its expression in naive CD4+ T cells and followed the in vitro differentiation of different T cell subsets. Although Th2, Th17, and induced Tregs (iTregs) exhibited modest levels of FoxO4 mRNA expression, FoxO4 expression was substantially higher in Th1 cells differentiated with IL-12 plus IL-2 (Figure 1A), suggesting an important role in Th1 cells. To better investigate the function of FoxO4 in T cells, we generated T cell–specific FoxO4-deficient mice (FoxO4fl/fl Cd4Cre mice; referred to hereafter as FoxO4-cKO) by breeding FoxO4fl/fl mice (23) with Cd4Cre-transgenic mice, and their FoxO4fl/fl littermates (referred to as WT) were used as controls in our studies. FoxO4-cKO mice, aged between 6 and 8 weeks, showed normal percentages of CD4+ single-positive (CD4 SP), CD8+ single-positive (CD8 SP), and CD4+CD8+ double-positive (CD4/8 DP) thymocytes as well as normal percentages and numbers of TCRβ+ cells (Figure 1, B and C, and Supplemental Figure 1, A–C; supplemental material available online with this article; https://doi.org/10.1172/JCI147566DS1), suggesting no major defect in TCR signaling during positive selection in FoxO4-cKO mice. Also, spleens from FoxO4-cKO mice had percentages and numbers of TCRβ+ cells similar to those of WT mouse spleens (Figure 1, D and E). Moreover, FoxO4-cKO mice did not exhibit a spontaneous inflammatory phenotype (data not shown). However, unlike FoxO1-deficient mice, FoxO4-cKO mice had slightly increased percentages and numbers of CD62L+ , but not CD44+, CD4+, or CD8+ T cells isolated from the spleens (Figure 1, D and E). In addition, CD4+Foxp3+ Tregs in spleens from FoxO4-cKO mice were present at percentages and numbers similar to those in WT mice (Figure 1, D and E). Thus, T cell development and homeostasis remained normal in T cell–specific FoxO4-deficient mice.

FoxO4 deficiency in CD4+ T cells has no apparent effect on T cell homeostasFigure 1

FoxO4 deficiency in CD4+ T cells has no apparent effect on T cell homeostasis. (A) Real-time qPCR analysis of FoxO4 mRNA in B6 naive CD4+CD44loCD62LhiCD25− T cells differentiated for 72 hours in Th1-, Th2-, Th17-, iTreg-, and Tfh-polarizing conditions. Results are presented relative to the expression of Gapdh mRNA. (B) Flow cytometric analysis of CD4 and CD8 expression in WT and FoxO4-cKO thymocytes (n = 10). The numbers adjacent to the outlined areas or in the quadrants indicate the percentage of cells. (C) Percentages of CD4 SP, CD8 SP, and CD4/8 DP cells in WT and FoxO4-cKO thymocytes (n = 10). (D) Flow cytometric analysis of B220, TCRβ, CD4 (gated on TCRβ+), CD8 (gated on TCRβ+), CD44 (gated on TCRβ+CD4+ or TCRβ+CD8+), CD62L (gated on TCRβ+CD4+or TCRβ+CD8+), and Foxp3 (gated on TCRβ+CD4+) expression on splenocytes isolated from WT and FoxO4-cKO mice (n = 10). SSC, side scatter. (E) Absolute numbers of total cells, B220+ B cells, TCRβ+ T cells, CD4+ T cells, CD8+ T cells and Foxp3+ T cells in spleens from WT and FoxO4-cKO mice (n = 10). Each symbol in C and E represents an individual mouse. NS, by unpaired, 2-tailed Student’s t test (C and E). Data are representative of 3 independent experiments with similar results (mean ±SD in A, C, and E).

FoxO4 negatively regulates IFN-γ production in Th1 cells in vitro. We next assessed the role of FoxO4 in CD4+ Th cell differentiation in vitro. We sorted CD4+CD25−CD62LhiCD44lo naive T cells by flow cytometry and differentiated them for 3–5 days in neutral (Th0), Th1, Th2, Th17, and iTreg conditions and then analyzed the lineage-specific markers by intracellular staining (Figure 2, A and B). We observed no significant difference in Th2, Th17, or iTreg differentiation. In addition, we also examined signature genes of Th2, Th17, and iTregs in corresponding skewed conditions. Consistent with the results of intracellular staining (Figure 2A and Supplemental Figure 2, A–D), real-time quantitative PCR analysis (qPCR) (Supplemental Figure 2, E–H) revealed no significant change in signature genes at the transcriptional level for these Th cell subsets. However, FoxO4 deficiency resulted in increased IFN-γ–producing cells in the Th0 condition, in the absence of exogenous IL-12. The result indicated that FoxO4 controlled IFN-γ production independently of IL-12 signaling (Figure 2A). Since FoxO3a deficiency has been shown to repress Th1 differentiation, we next examined Th1 differentiation in FoxO4-

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