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The mTOR kinase differentially regulates effector and regulatory T cell lineage commitment
Greg M Delgoffe1, Thomas P Kole, Yan Zheng
1Sidney-Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
Immunity
|June 23, 2009
Summary
The mechanistic target of rapamycin (mTOR) pathway is crucial for T cell differentiation into effector cells. mTOR deficiency leads to regulatory T cell development instead of effector T cell fates.
Area of Science:
- Immunology
- Cell Biology
- Molecular Biology
Background:
- Effector T cell differentiation is a complex process involving integration of diverse cytokine signals.
- The mechanistic target of rapamycin (mTOR) pathway's role in T cell fate determination is not fully understood.
Purpose of the Study:
- To investigate the role of mTOR signaling in dictating T cell differentiation outcomes.
- To elucidate the molecular mechanisms by which mTOR influences T cell lineage commitment.
Main Methods:
- Generated T cells deficient in mTOR signaling.
- Analyzed T cell activation, cytokine production, and transcription factor activation (STATs, Foxp3, Smad3).
- Utilized genetic manipulation to assess the roles of TORC1 and TORC2 complexes.
Main Results:
- mTOR-deficient T cells showed normal initial activation but failed to differentiate into Th1, Th2, or Th17 effector cells.
- This differentiation failure was linked to reduced STAT activation and impaired expression of lineage-specific transcription factors.
- T cells lacking mTOR preferentially differentiated into regulatory T cells (Foxp3+), associated with hyperactive Smad3 signaling.
- Selective deficiency in TORC1 did not induce regulatory T cell differentiation, suggesting roles for both TORC1 and TORC2.
Conclusions:
- mTOR kinase signaling is a critical regulator of the decision between effector and regulatory T cell lineage commitment.
- mTOR signaling pathways, including both TORC1 and TORC2, are essential for preventing T cell diversion towards a regulatory fate.
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