Impaired glycolysis reduces mitochondrial translocation of mTORC2 and shifts iNKT cell functions. Mus musculus

Recent studies critically link metabolism to immunity. However, the underlying mechanisms are still unclear. NKT cells, as innate-like T lymphocytes, are phenotypically and functionally different from conventional T cells. The cellular metabolism and its role in controlling NKT cell functions have not been characterized. Here, we show that fresh isolated NKT cells possess much lower maximal respiratory capacity but higher glycolytic capacity than conventional CD4 T cells. Upon activation, NKT cells increase aerobic glycolysis and oxidative phosphorylation (OXPHOS), and glycolysis is the predominant bioenergetic pathway. Hexokinase-II (HK-II), a major contributor to aerobic glycolysis, binds to mitochondria and controls activation of mTORC2 (mammalian target of rapamycin complex 2), which activates Akt and PKC and promotes TCR recycling. Sustained TCR signaling is required for optimal IFN- production in NKT cells. Thus, dissociation of HK-II from mitochondria inhibits TCR recycling and polarizes NKT cell functions toward Th2. Our studies demonstrate how glycolysis influences NKT cell functions.