Research ArticleImmunometabolism

Immunometabolism regulates TCR recycling and iNKT cell functions

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Science Signaling  26 Feb 2019:
Vol. 12, Issue 570, eaau1788
DOI: 10.1126/scisignal.aau1788

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Glycolysis promotes recycling

Lymphocyte functions are linked to activation of cellular metabolic pathways. Yet, it remains unclear how metabolism influences the activity of invariant natural killer T (iNKT) cells, which express a T cell receptor with limited diversity. Fu et al. found that effector iNKT cells from the spleen and liver, which had an activated cell surface phenotype, were more glycolytic than naïve CD4+ T cells. T cell receptor stimulation of iNKT cells further increased glycolysis, which promoted the production of the proinflammatory cytokine interferon-γ. Pharmacological inhibitors of glycolysis reduced T cell receptor signaling and recycling to sites of antigen recognition at the cell surface. Thus, glycolysis may augment iNKT cell activation by sustaining the density of cell surface T cell receptor.

Abstract

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.

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