Asymmetric inheritance of mTORC1 kinase activity during division dictates CD8(+) T cell differentiation

Nat Immunol. 2016 Jun;17(6):704-11. doi: 10.1038/ni.3438. Epub 2016 Apr 11.

Abstract

The asymmetric partitioning of fate-determining proteins has been shown to contribute to the generation of CD8(+) effector and memory T cell precursors. Here we demonstrate the asymmetric partitioning of mTORC1 activity after the activation of naive CD8(+) T cells. This results in the generation of two daughter T cells, one of which shows increased mTORC1 activity, increased glycolytic activity and increased expression of effector molecules. The other daughter T cell has relatively low mTORC1 activity and increased lipid metabolism, expresses increased amounts of anti-apoptotic molecules and subsequently displays enhanced long-term survival. Mechanistically, we demonstrate a link between T cell antigen receptor (TCR)-induced asymmetric expression of amino acid transporters and RagC-mediated translocation of mTOR to the lysosomes. Overall, our data provide important insight into how mTORC1-mediated metabolic reprogramming affects the fate decisions of T cells.

MeSH terms

  • Animals
  • CD8-Positive T-Lymphocytes / immunology*
  • Cell Differentiation
  • Cell Division / immunology*
  • Cell Survival
  • Cells, Cultured
  • Female
  • Glycolysis
  • Immunologic Memory
  • Lipid Metabolism
  • Lysosomes / metabolism*
  • Male
  • Mechanistic Target of Rapamycin Complex 1
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Multiprotein Complexes / metabolism*
  • Precursor Cells, T-Lymphoid / immunology*
  • Protein Transport
  • Receptors, Antigen, T-Cell / metabolism
  • Signal Transduction
  • TOR Serine-Threonine Kinases / metabolism*

Substances

  • Multiprotein Complexes
  • Receptors, Antigen, T-Cell
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1