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

• Published in: Nature immunology Vol. 17; no. 6; pp. 704 - 711
• Main Authors: Pollizzi, Kristen N, Sun, Im-Hong, Patel, Chirag H, Lo, Ying-Chun, Oh, Min-Hee, Waickman, Adam T, Tam, Ada J, Blosser, Richard L, Wen, Jiayu, Delgoffe, Greg M, Powell, Jonathan D
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.06.2016; Nature Publishing Group
• Subjects: 13/106; 13/95; 14/19; 38/39; 45/90; 631/250/2152/1566/1571; 631/250/2152/1566/2493; 64/60; 82/80; Amino acids; Animals; Biomedicine; CD8-Positive T-Lymphocytes - immunology; Cell Differentiation; Cell Division - immunology; Cell Survival; Cells, Cultured; Female; Glycolysis; Immunologic Memory; Immunology; Infectious Diseases; 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; Survival; TOR Serine-Threonine Kinases - metabolism; Translocation
• ISSN: 1529-2908; 1529-2916; 1529-2916
• DOI: 10.1038/ni.3438

Asymmetric division can generate effector and memory CD8 + T cell precursors. Powell and colleagues show asymmetric partitioning of mTORC1 activity upon CD8 + T cell division, which results in distinct metabolic programming of daughter T cells. 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.