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A role for mammalian target of rapamycin in regulating T cell activation versus anergy

Yan Zheng1, Samuel L Collins, Michael A Lutz

  • 1The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University Medical Institutions, Baltimore, MD 21231, USA.

Journal of Immunology (Baltimore, Md. : 1950)
|February 6, 2007
PubMed

Insights

The mammalian target of rapamycin (mTOR) integrates signals to control T cell activation versus anergy. mTOR activation promotes immune responses, while inhibition leads to T cell anergy, impacting adaptive immunity.

Area of Science:

  • Immunology
  • Cellular Signaling
  • Molecular Biology

Background:

  • T cell activation outcome depends on multiple signals beyond T cell receptor (TCR) engagement.
  • The mammalian target of rapamycin (mTOR) pathway is a key regulator of cellular processes, including immune responses.

Purpose of the Study:

  • To investigate the role of mTOR in integrating signals that determine T cell activation or anergy following TCR engagement.
  • To elucidate the molecular mechanisms by which mTOR influences T cell fate.

Main Methods:

  • In vitro experiments assessing T cell responses under varying mTOR activity (activation vs. inhibition).
  • Analysis of downstream mTOR signaling markers, including S6 kinase 1 phosphorylation and CD71 expression.
  • In vivo studies evaluating T cell anergy induction with mTOR inhibition.
  • Genetic engineering of T cells to confer rapamycin resistance to mTOR.

Main Results:

  • mTOR activation in vitro promotes full T cell activation and immune responses.
  • mTOR inhibition in vitro induces T cell anergy, characterized by reduced S6 kinase 1 phosphorylation and CD71 expression.
  • Reversal of anergy is linked to specific mTOR activation, not proliferation.
  • Rapamycin-resistant mTOR renders T cells resistant to anergy induction.
  • In vivo, mTOR inhibition promotes T cell anergy and CD71 expression can distinguish anergic from activated T cells.

Conclusions:

  • mTOR acts as a central integrator of environmental cues and accessory signals to dictate the outcome of TCR engagement.
  • mTOR signaling is critical for determining T cell fate, promoting either activation or anergy.
  • Targeting mTOR may offer therapeutic strategies for modulating immune responses.

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