Metabolic regulation of T cell development by Sin1-mTORC2 is mediated by pyruvate kinase M2

Glucose metabolism plays a key role in thymocyte development. The mammalian target of rapamycin complex 2 (mTORC2) is a critical regulator of cell growth and metabolism, but its role in early thymocyte development and metabolism has not been fully studied. We show here that genetic ablation of Sin1, an essential component of mTORC2, in T lineage cells results in severely impaired thymocyte development at the CD4 ' CD8 ' double negative (DN) stages but not at the CD4 + CD8 + double positive (DP) or later stages. Notably, Sin1-deficient DN thymocytes show markedly reduced proliferation and glycolysis. Importantly, we discover that the M2 isoform of pyruvate kinase (PKM2) is a novel and crucial Sin1 effector in promoting DN thymocyte development and metabolism. At the molecular level, we show that Sin1-mTORC2 controls PKM2 expression through an AKT-dependent PPAR- 3 nuclear translocation. Together, our study unravels a novel mTORC2 'PPAR- 3 'PKM2 pathway in immune-metabolic regulation of early thymocyte development.