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mTORC1 couples immune signals and metabolic programming to establish T(reg)-cell function
Hu Zeng1, Kai Yang, Caryn Cloer
1Department of Immunology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Nature
|July 2, 2013
Summary
Mechanistic target of rapamycin complex 1 (mTORC1) signaling is crucial for regulatory T-cell (Treg) function. Disrupting mTORC1 impairs Treg suppressive activity, leading to fatal inflammation in mice.
Area of Science:
- Immunology
- Cellular Metabolism
- Molecular Biology
Background:
- The mechanistic target of rapamycin (mTOR) pathway integrates immune and metabolic signals to regulate T-cell differentiation and function.
- While mTOR signaling impacts effector CD4+ T cells and T(reg) cell differentiation, its role in T(reg) cell homeostasis and function is less understood.
Purpose of the Study:
- To investigate the role of mTOR complex 1 (mTORC1) signaling in the function and homeostasis of regulatory T-cells (T(reg)).
Main Methods:
- Utilized Treg-specific deletion of raptor in mice to disrupt mTORC1 signaling.
- Assessed T(reg) cell suppressive activity, proliferation, and metabolic pathways.
- Analyzed the expression of key molecules like Foxp3, CTLA4, and ICOS.
Main Results:
- Treg cells exhibit higher steady-state mTORC1 activity than naive T cells, driven by T-cell receptor (TCR) and IL-2 signals.
- Disruption of mTORC1 in Tregs led to a loss of suppressive function and fatal inflammatory disease.
- mTORC1 signaling promotes Treg proliferation and CTLA4/ICOS expression via the mevalonate pathway, independent of Foxp3 levels.
Conclusions:
- mTORC1 is a critical positive regulator of Treg cell function, linking TCR/IL-2 signals to metabolic pathways.
- mTORC1 signaling is essential for maintaining immune homeostasis and tolerance by programming Treg suppressive activity.
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