Immunometabolism regulates TCR recycling and iNKT cell functions

Invariant natural killer T (iNKT) cells are innate-like T lymphocytes that express an invariant T cell receptor (TCR), which recognizes glycolipid antigens presented on CD1d molecules. These cells are phenotypically and functionally distinct from conventional T cells. When we characterized the metabolic activity of iNKT cells, consistent with their activated phenotype, we found that they had much less mitochondrial respiratory capacity but increased glycolytic activity in comparison to naïve conventional CD4⁺ T cells. After TCR engagement, iNKT cells further increased aerobic glycolysis, which was important for the expression of interferon-γ (IFN-γ). Glycolytic metabolism promoted the translocation of hexokinase-II to mitochondria and the activation of mammalian target of rapamycin complex 2 (mTORC2). Inhibiting glycolysis reduced the activity of Akt and PKCθ, which inhibited TCR recycling and accumulation within the immune synapse. Diminished TCR accumulation in the immune synapse reduced the activation of proximal and distal TCR signaling pathways and IFN-γ production in activated iNKT cells. Our studies demonstrate that glycolytic metabolism augments TCR signaling duration and IFN-γ production in iNKT cells by increasing TCR recycling.