Nature immunology, 2021-02, Vol.22 (2), p.193-204
2021
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- Autor(en) / Beteiligte
- Titel
- NF-κB-inducing kinase maintains T cell metabolic fitness in antitumor immunity
- Ist Teil von
- Nature immunology, 2021-02, Vol.22 (2), p.193-204
- Ort / Verlag
- United States
- Erscheinungsjahr
- 2021
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1529-2908eISSN: 1529-2916DOI: 10.1038/s41590-020-00829-6Titel-ID: cdi_pubmed_primary_33398181
- Format
- –
- Schlagworte
- Animals, CD8-Positive T-Lymphocytes - enzymology, CD8-Positive T-Lymphocytes - immunology, CD8-Positive T-Lymphocytes - transplantation, Cell Line, Tumor, Colonic Neoplasms - enzymology, Colonic Neoplasms - immunology, Colonic Neoplasms - pathology, Colonic Neoplasms - therapy, Cytotoxicity, Immunologic, Energy Metabolism, Enzyme Stability, Female, Glucosephosphate Dehydrogenase - metabolism, Glycolysis, Hexokinase - genetics, Hexokinase - metabolism, Immunotherapy, Adoptive, Lymphocyte Activation, Lymphocytes, Tumor-Infiltrating - enzymology, Lymphocytes, Tumor-Infiltrating - immunology, Lymphocytes, Tumor-Infiltrating - transplantation, Male, Melanoma, Experimental - enzymology, Melanoma, Experimental - immunology, Melanoma, Experimental - pathology, Melanoma, Experimental - therapy, Mice, Inbred C57BL, Mice, Knockout, NADP - metabolism, NF-kappaB-Inducing Kinase, Phenotype, Protein Serine-Threonine Kinases - deficiency, Protein Serine-Threonine Kinases - genetics, Protein Serine-Threonine Kinases - metabolism, Reactive Oxygen Species - metabolism, Signal Transduction, Tumor Microenvironment