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J Exp Med. 2017 May 1;214(5):1493-1507. doi: 10.1084/jem.20161524. Epub 2017 Mar 29.

The kinase TBK1 functions in dendritic cells to regulate T cell homeostasis, autoimmunity, and antitumor immunity.

Xiao Y1,2, Zou Q3,2, Xie X2, Liu T2,4, Li HS2, Jie Z2, Jin J2,5, Hu H2,4, Manyam G6, Zhang L6,7, Cheng X2, Wang H2, Marie I8,9,10, Levy DE8, Watowich SS2,11, Sun SC12,11.

Author information

1
Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences/Shanghai Jiao Tong University School of Medicine, Shanghai 200031, China.
2
Department of Immunology, MD Anderson Cancer Center, The University of Texas, Houston, TX 77030.
3
Department of Immunology and Microbiology, Shanghai Institute of Immunology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
4
State Key Laboratory of Biotherapy, West China Hospital, Si-Chuan University and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China.
5
Life Sciences Institute, Zhejiang University, Hangzhou 310058, China.
6
Department of Bioinformatics and Computational Biology, MD Anderson Cancer Center, The University of Texas, Houston, TX 77030.
7
Department of Environmental Health, University of Cincinnati, Cincinnati, OH 45220.
8
Department of Pathology, NYU School of Medicine, New York, NY 10016.
9
Department of Microbiology, NYU School of Medicine, New York, NY 10016.
10
NYU Cancer Institute, NYU School of Medicine, New York, NY 10016.
11
Graduate School of Biomedical Sciences, The University of Texas, Houston, TX 77030.
12
Department of Immunology, MD Anderson Cancer Center, The University of Texas, Houston, TX 77030 ssun@mdanderson.org.

Abstract

Dendritic cells (DCs) are crucial for mediating immune responses but, when deregulated, also contribute to immunological disorders, such as autoimmunity. The molecular mechanism underlying the function of DCs is incompletely understood. In this study, we have identified TANK-binding kinase 1 (TBK1), a master innate immune kinase, as an important regulator of DC function. DC-specific deletion of Tbk1 causes T cell activation and autoimmune symptoms and also enhances antitumor immunity in animal models of cancer immunotherapy. The TBK1-deficient DCs have up-regulated expression of co-stimulatory molecules and increased T cell-priming activity. We further demonstrate that TBK1 negatively regulates the induction of a subset of genes by type I interferon receptor (IFNAR). Deletion of IFNAR1 could largely prevent aberrant T cell activation and autoimmunity in DC-conditional Tbk1 knockout mice. These findings identify a DC-specific function of TBK1 in the maintenance of immune homeostasis and tolerance.

PMID:
28356390
PMCID:
PMC5413337
DOI:
10.1084/jem.20161524
[Indexed for MEDLINE]
Free PMC Article

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