The Interleukin-2-mTORc1 Kinase Axis Defines the Signaling, Differentiation, and Metabolism of T Helper 1 and Follicular B Helper T Cells

Immunity. 2015 Oct 20;43(4):690-702. doi: 10.1016/j.immuni.2015.08.017. Epub 2015 Sep 22.

Abstract

The differentiation of CD4(+) helper T cell subsets with diverse effector functions is accompanied by changes in metabolism required to meet their bioenergetic demands. We find that follicular B helper T (Tfh) cells exhibited less proliferation, glycolysis, and mitochondrial respiration, accompanied by reduced mTOR kinase activity compared to T helper 1 (Th1) cells in response to acute viral infection. IL-2-mediated activation of the Akt kinase and mTORc1 signaling was both necessary and sufficient to shift differentiation away from Tfh cells, instead promoting that of Th1 cells. These findings were not the result of generalized signaling attenuation in Tfh cells, because they retained the ability to flux calcium and activate NFAT-transcription-factor-dependent cytokine production. These data identify the interleukin-2 (IL-2)-mTORc1 axis as a critical orchestrator of the reciprocal balance between Tfh and Th1 cell fates and their respective metabolic activities after acute viral infection.

Publication types

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

MeSH terms

  • Animals
  • Apoptosis
  • Calcium Signaling
  • Cell Cycle
  • Cell Division
  • Enzyme Activation
  • Glucose / metabolism
  • Glycolysis
  • Interleukin-2 / physiology*
  • Interleukin-2 Receptor alpha Subunit / physiology
  • Lymphocytic choriomeningitis virus / immunology
  • Mechanistic Target of Rapamycin Complex 1
  • Mice, Inbred C57BL
  • Multiprotein Complexes / physiology*
  • NFATC Transcription Factors / physiology
  • Oxygen Consumption
  • Positive Regulatory Domain I-Binding Factor 1
  • Proto-Oncogene Proteins c-akt / physiology*
  • Signal Transduction / physiology*
  • Specific Pathogen-Free Organisms
  • T-Lymphocyte Subsets / cytology
  • T-Lymphocyte Subsets / immunology
  • T-Lymphocyte Subsets / metabolism*
  • T-Lymphocytes, Helper-Inducer / cytology
  • T-Lymphocytes, Helper-Inducer / immunology
  • T-Lymphocytes, Helper-Inducer / metabolism*
  • T-Lymphocytes, Helper-Inducer / virology
  • TOR Serine-Threonine Kinases / physiology*
  • Th1 Cells / cytology
  • Th1 Cells / immunology
  • Th1 Cells / metabolism
  • Transcription Factors / biosynthesis
  • Transcription Factors / genetics

Substances

  • Il2ra protein, mouse
  • Interleukin-2
  • Interleukin-2 Receptor alpha Subunit
  • Multiprotein Complexes
  • NFATC Transcription Factors
  • Prdm1 protein, mouse
  • Transcription Factors
  • Positive Regulatory Domain I-Binding Factor 1
  • TOR Serine-Threonine Kinases
  • Akt1 protein, mouse
  • Mechanistic Target of Rapamycin Complex 1
  • Proto-Oncogene Proteins c-akt
  • Glucose

Associated data

  • GEO/GSE55596