Immunity (Cambridge, Mass.), 2021-05, Vol.54 (5), p.976-987.e7
2021
Details
- Autor(en) / Beteiligte
- Titel
- Glycolytic ATP fuels phosphoinositide 3-kinase signaling to support effector T helper 17 cell responses
- Ist Teil von
- Immunity (Cambridge, Mass.), 2021-05, Vol.54 (5), p.976-987.e7
- Ort / Verlag
- United States: Elsevier Limited
- Erscheinungsjahr
- 2021
- Link zum Volltext
- Quelle
- EZB Electronic Journals Library
- Beschreibungen/Notizen
- Aerobic glycolysis-the Warburg effect-converts glucose to lactate via the enzyme lactate dehydrogenase A (LDHA) and is a metabolic feature of effector T cells. Cells generate ATP through various mechanisms and Warburg metabolism is comparatively an energy-inefficient glucose catabolism pathway. Here, we examined the effect of ATP generated via aerobic glycolysis in antigen-driven T cell responses. Cd4 Ldha mice were resistant to Th17-cell-mediated experimental autoimmune encephalomyelitis and exhibited defective T cell activation, migration, proliferation, and differentiation. LDHA deficiency crippled cellular redox balance and inhibited ATP production, diminishing PI3K-dependent activation of Akt kinase and thereby phosphorylation-mediated inhibition of Foxo1, a transcriptional repressor of T cell activation programs. Th17-cell-specific expression of an Akt-insensitive Foxo1 recapitulated the defects seen in Cd4 Ldha mice. Induction of LDHA required PI3K signaling and LDHA deficiency impaired PI3K-catalyzed PIP3 generation. Thus, Warburg metabolism augments glycolytic ATP production, fueling a PI3K-centered positive feedback regulatory circuit that drives effector T cell responses.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1074-7613eISSN: 1097-4180DOI: 10.1016/j.immuni.2021.04.008Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_8130647
- Format
- –
- Schlagworte
- 1-Phosphatidylinositol 3-kinase, Ablation, Adenosine Triphosphate - metabolism, AKT protein, Animals, Antigens, ATP, Catabolism, Cell activation, Cell differentiation, Cell Differentiation - physiology, Cell division, Cell growth, Cell Line, Cell migration, Cell Proliferation - physiology, Circuits, Cytokines, Dehydrogenases, Effector cells, Energy metabolism, Epigenetics, Experimental allergic encephalomyelitis, Female, FOXO1 protein, Gene expression, Gene Expression Regulation, Neoplastic - physiology, Glucose, Glucose - metabolism, Glycogen Storage Disease - metabolism, Glycolysis, Glycolysis - physiology, Helper cells, Kinases, L-Lactate dehydrogenase, L-Lactate Dehydrogenase - deficiency, L-Lactate Dehydrogenase - metabolism, Lactate dehydrogenase, Lactic acid, Lymphocytes, Lymphocytes T, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Peptides, Phosphatidylinositol 3,4,5-triphosphate, Phosphatidylinositol 3-Kinase - metabolism, Phosphorylation, Positive feedback, Signal Transduction - physiology, Signaling, Spinal cord, T cell receptors, Th17 Cells - metabolism, Transcription, Transcription factors