Metabolic maintenance of cell asymmetry following division in activated T lymphocytes

Nature. 2016 Apr 21;532(7599):389-93. doi: 10.1038/nature17442. Epub 2016 Apr 11.

Abstract

Asymmetric cell division, the partitioning of cellular components in response to polarizing cues during mitosis, has roles in differentiation and development. It is important for the self-renewal of fertilized zygotes in Caenorhabditis elegans and neuroblasts in Drosophila, and in the development of mammalian nervous and digestive systems. T lymphocytes, upon activation by antigen-presenting cells (APCs), can undergo asymmetric cell division, wherein the daughter cell proximal to the APC is more likely to differentiate into an effector-like T cell and the distal daughter is more likely to differentiate into a memory-like T cell. Upon activation and before cell division, expression of the transcription factor c-Myc drives metabolic reprogramming, necessary for the subsequent proliferative burst. Here we find that during the first division of an activated T cell in mice, c-Myc can sort asymmetrically. Asymmetric distribution of amino acid transporters, amino acid content, and activity of mammalian target of rapamycin complex 1 (mTORC1) is correlated with c-Myc expression, and both amino acids and mTORC1 activity sustain the differences in c-Myc expression in one daughter cell compared to the other. Asymmetric c-Myc levels in daughter T cells affect proliferation, metabolism, and differentiation, and these effects are altered by experimental manipulation of mTORC1 activity or c-Myc expression. Therefore, metabolic signalling pathways cooperate with transcription programs to maintain differential cell fates following asymmetric T-cell division.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Transport Systems / metabolism
  • Amino Acids / metabolism
  • Animals
  • CD8-Positive T-Lymphocytes / cytology*
  • CD8-Positive T-Lymphocytes / metabolism*
  • Cell Differentiation / genetics
  • Cell Division*
  • Cell Polarity* / genetics
  • Female
  • Lymphocyte Activation*
  • Male
  • Mechanistic Target of Rapamycin Complex 1
  • Mice
  • Multiprotein Complexes / metabolism
  • Proto-Oncogene Proteins c-myc / genetics
  • Proto-Oncogene Proteins c-myc / metabolism
  • Signal Transduction / genetics
  • TOR Serine-Threonine Kinases / metabolism
  • Transcription, Genetic

Substances

  • Amino Acid Transport Systems
  • Amino Acids
  • Multiprotein Complexes
  • Myc protein, mouse
  • Proto-Oncogene Proteins c-myc
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1