The mTOR kinase differentially regulates effector and regulatory T cell lineage commitment

Immunity. 2009 Jun 19;30(6):832-44. doi: 10.1016/j.immuni.2009.04.014.

Abstract

Effector T cell differentiation requires the simultaneous integration of multiple, and sometimes opposing, cytokine signals. We demonstrated mTOR's role in dictating the outcome of T cell fate. mTOR-deficient T cells displayed normal activation and IL-2 production upon initial stimulation. However, such cells failed to differentiate into T helper 1 (Th1), Th2, or Th17 effector cells. The inability to differentiate was associated with decreased STAT transcription factor activation and failure to upregulate lineage-specific transcription factors. Under normally activating conditions, T cells lacking mTOR differentiated into Foxp3(+) regulatory T cells. This was associated with hyperactive Smad3 activation in the absence of exogenous TGF-beta. Surprisingly, T cells selectively deficient in TORC1 do not divert to a regulatory T cell pathway, implicating both TORC1 and TORC2 in preventing the generation of regulatory T cells. Overall, our studies suggest that mTOR kinase signaling regulates decisions between effector and regulatory T cell lineage commitment.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Carrier Proteins / genetics
  • Carrier Proteins / immunology
  • Carrier Proteins / metabolism*
  • Cell Differentiation / immunology*
  • Interleukin-2 / biosynthesis
  • Interleukin-2 / immunology
  • Mice
  • Mice, Knockout
  • Phosphotransferases (Alcohol Group Acceptor) / genetics
  • Phosphotransferases (Alcohol Group Acceptor) / immunology
  • Phosphotransferases (Alcohol Group Acceptor) / metabolism*
  • Receptors, Antigen, T-Cell / immunology
  • Receptors, Antigen, T-Cell / metabolism
  • STAT Transcription Factors / immunology
  • STAT Transcription Factors / metabolism
  • Signal Transduction / immunology
  • T-Lymphocytes, Helper-Inducer / enzymology
  • T-Lymphocytes, Helper-Inducer / immunology*
  • T-Lymphocytes, Regulatory / enzymology
  • T-Lymphocytes, Regulatory / immunology*
  • TOR Serine-Threonine Kinases
  • Trans-Activators / immunology*
  • Trans-Activators / metabolism
  • Transcription Factors / genetics
  • Transcription Factors / immunology*
  • Transcription Factors / metabolism
  • Transforming Growth Factor beta / immunology
  • Transforming Growth Factor beta / metabolism

Substances

  • Carrier Proteins
  • Crtc1 protein, mouse
  • Crtc2 protein, mouse
  • Interleukin-2
  • Receptors, Antigen, T-Cell
  • STAT Transcription Factors
  • Trans-Activators
  • Transcription Factors
  • Transforming Growth Factor beta
  • Phosphotransferases (Alcohol Group Acceptor)
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse