Open AccessNF-κB-inducing kinase maintains T cell metabolic fitness in antitumor immunity
Author(s) -
Meidi Gu,
Xiaofei Zhou,
Jin Ho Sohn,
Lele Zhu,
Zuliang Jie,
Jin Yang,
Xiaofeng Zheng,
Xiaoping Xie,
Jie Yang,
Yi Shi,
Hans D. Brightbill,
Jae Bum Kim,
Jing Wang,
Xuhong Cheng,
Shao Cong Sun
Publication year - 2021
Publication title -
nature immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 9.074
H-Index - 388
eISSN - 1529-2916
pISSN - 1529-2908
DOI - 10.1038/s41590-020-00829-6
Subject(s) - microbiology and biotechnology , glycolysis , biology , tumor microenvironment , t cell , immune system , cytotoxic t cell , effector , anaerobic glycolysis , cd8 , kinase , ctl* , metabolism , biochemistry , immunology , in vitro
Metabolic reprograming toward aerobic glycolysis is a pivotal mechanism shaping immune responses. Here we show that deficiency in NF-κB-inducing kinase (NIK) impairs glycolysis induction, rendering CD8 + effector T cells hypofunctional in the tumor microenvironment. Conversely, ectopic expression of NIK promotes CD8 + T cell metabolism and effector function, thereby profoundly enhancing antitumor immunity and improving the efficacy of T cell adoptive therapy. NIK regulates T cell metabolism via a NF-κB-independent mechanism that involves stabilization of hexokinase 2 (HK2), a rate-limiting enzyme of the glycolytic pathway. NIK prevents autophagic degradation of HK2 through controlling cellular reactive oxygen species levels, which in turn involves modulation of glucose-6-phosphate dehydrogenase (G6PD), an enzyme that mediates production of the antioxidant NADPH. We show that the G6PD-NADPH redox system is important for HK2 stability and metabolism in activated T cells. These findings establish NIK as a pivotal regulator of T cell metabolism and highlight a post-translational mechanism of metabolic regulation.