| First Author | Gu M | Year | 2021 |
| Journal | Nat Immunol | Volume | 22 |
| Issue | 2 | Pages | 193-204 |
| PubMed ID | 33398181 | Mgi Jnum | J:305264 |
| Mgi Id | MGI:6705805 | Doi | 10.1038/s41590-020-00829-6 |
| Citation | Gu M, et al. (2021) NF-kappaB-inducing kinase maintains T cell metabolic fitness in antitumor immunity. Nat Immunol 22(2):193-204 |
| abstractText | Metabolic reprograming toward aerobic glycolysis is a pivotal mechanism shaping immune responses. Here we show that deficiency in NF-kappaB-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-kappaB-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. |
