Abstract

The cytokine IL-15 mediates development and survival of immune cells, including natural killer T (NKT) cells, but the underlying mechanism of IL-15 function is incompletely understood. Here we show that IL-15 induces autophagy in NKT cells with a mechanism that involves a crucial signaling component, TBK-binding protein 1 (Tbkbp1). Tbkbp1 facilitates activation of the autophagy-initiating kinase Ulk1 through antagonizing the inhibitory action of mTORC1. This antagonization involves the recruitment of an mTORC1-opposing phosphatase to Ulk1. Tbkbp1 deficiency attenuates IL-15-stimulated NKT cell autophagy, and is associated with mitochondrial dysfunction, aberrant ROS production, defective Bcl2 expression and reduced NKT cell survival. Consequently, Tbkbp1-deficient mice have profound deficiency in NKT cells, especially IFN-γ-producing NKT1. We further show that Tbkbp1 regulates IL-15-stimulated autophagy and survival of NK cells. These findings suggest a mechanism of autophagy induction by IL-15, and establish Tbkbp1 as a regulator of NKT cell development and survival.

Details

Title
TBK-binding protein 1 regulates IL-15-induced autophagy and NKT cell survival
Author
Zhu, Lele 1 ; Xie, Xiaoping 1 ; Zhang, Lingyun 2 ; Wang, Hui 3   VIAFID ORCID Logo  ; Zuliang Jie 1 ; Zhou, Xiaofei 1 ; Shi, Jianhong 4 ; Zhao, Shuli 5 ; Zhang, Boxiang 6 ; Cheng, Xuhong 1 ; Shao-Cong, Sun 7 

1  Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 
2  Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Center for Reproductive Medicine, Henan Key Laboratory of Reproduction and Genetics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450000, China 
3  Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, China 
4  Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Central Laboratory, Affiliated Hospital of Hebei University, Baoding, China 
5  Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; General Clinical Research Center, Nanjing First hospital, Nanjing Medical University, Nanjing, Jiangsu, 210012, China 
6  Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department Two of Thoracic Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, 710061, China 
7  Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; The University of Texas Graduate School of Biomedical Sciences, Houston, TX, USA 
Pages
1-14
Publication year
2018
Publication date
Jul 2018
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-018-05097-5
ProQuest document ID
2071541738
Copyright
© 2018. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.