NF-κB-inducing kinase maintains T cell metabolic fitness in antitumor immunity
- 4 January 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Immunology
- Vol. 22 (2), 193-204
- https://doi.org/10.1038/s41590-020-00829-6
Abstract
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.Keywords
Funding Information
- U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (GM84459)
- National Research Foundation of South Korean
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