PDK1 regulation of mTOR and hypoxia-inducible factor 1 integrate metabolism and migration of CD8 ⁺ T cells

Abstract

A PI3K- and Akt-independent pathway mediated by mTORC1 regulates expression of HIF1 in CD8 ⁺ T cells and is required to sustain glucose metabolism and regulate cell trafficking.

Abstract

mTORC1 (mammalian target of rapamycin complex 1) controls transcriptional programs that determine CD8 ⁺ cytolytic T cell (CTL) fate. In some cell systems, mTORC1 couples phosphatidylinositol-3 kinase (PI3K) and Akt to the control of glucose uptake and glycolysis. However, PI3K–Akt-independent mechanisms control glucose metabolism in CD8 ⁺ T cells, and the role of mTORC1 has not been explored. The present study now demonstrates that mTORC1 activity in CD8 ⁺ T cells is not dependent on PI3K or Akt but is critical to sustain glucose uptake and glycolysis in CD8 ⁺ T cells. We also show that PI3K- and Akt-independent pathways mediated by mTORC1 regulate the expression of HIF1 (hypoxia-inducible factor 1) transcription factor complex. This mTORC1–HIF1 pathway is required to sustain glucose metabolism and glycolysis in effector CTLs and strikingly functions to couple mTORC1 to a diverse transcriptional program that controls expression of glucose transporters, multiple rate-limiting glycolytic enzymes, cytolytic effector molecules, and essential chemokine and adhesion receptors that regulate T cell trafficking. These data reveal a fundamental mechanism linking nutrient and oxygen sensing to transcriptional control of CD8 ⁺ T cell differentiation.