mTORC1 couples immune signals and metabolic programming to establish Treg cell function
By H. Zeng, Kai Yang, Caryn M. Cloer, G. Neale, P. Vogel, Hongbo Chi. Nature, 2013
751 citations recorded by the source corpus.
The mechanistic target of rapamycin (mTOR) pathway integrates diverse environmental inputs, including immune signals and metabolic cues, to direct T-cell fate decisions. The activation of mTOR, which is the catalytic subunit of the mTORC1 and mTORC2 complexes, delivers an obligatory signal for the proper activation and differentiation of effector CD4+ T cells, whereas in the regulatory T-cell (Treg) compartment, the Akt–mTOR axis is widely acknowledged as a crucial negative regulator of Treg-cell de novo differentiation and population expansion. However, whether mTOR signalling affects the homeostasis and function of Treg cells remains largely unexplored. Here we show that mTORC1 signalling is a pivotal positive determinant of Treg-cell function in mice. Treg cells have elevated steady-state mTORC1 activity compared to naive T cells. Signals through the T-cell antigen receptor (TCR) and interleukin-2 (IL-2) provide major inputs for mTORC1 activation, which in turn programs the suppressive function of Treg cells. Disruption of mTORC1 through Treg-specific deletion of the essential component raptor leads to a profound loss of Treg-cell suppressive activity in vivo and the development of a fatal early onset inflammatory disorder. Mechanistically, raptor/mTORC1 signalling in Treg cells promotes cholesterol and lipid metabolism, with the mevalonate pathway particularly important for coordinating Treg-cell proliferation and upregulation of the suppressive molecules CTLA4 and ICOS to establish Treg-cell functional competency. By contrast, mTORC1 does not directly affect the expression of Foxp3 or anti- and pro-inflammatory cytokines in Treg cells, suggesting a non-conventional mechanism for Treg-cell functional regulation. Finally, we provide evidence that mTORC1 maintains Treg-cell function partly through inhibiting the mTORC2 pathway. Our results demonstrate that mTORC1 acts as a fundamental ‘rheostat’ in Treg cells to link immunological signals from TCR and IL-2 to lipogenic pathways and functional fitness, and highlight a central role of metabolic programming of Treg-cell suppressive activity in immune homeostasis and tolerance.
Subfields: Immunology
View Paper: https://www.semanticscholar.org/paper/6ff2523e7c4b8afd3fb65be103a5a2b016d8be99
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In Immunology
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Citations in the corpus
- Immunological Effects of Conventional Chemotherapy and Targeted Anticancer Agents. (2015, background): “Obviously, subverting the capacity ofmethotrexate (Cribbs et al., 2015) or rapamycin (Zeng et al., 2013) to expand TREG cells may significantly improve the antineoplastic effects of these drugs (Wang et al., 2014).”
- T cell metabolism drives immunity (2015, background): “PTEN (phosphatase and tensin homologue) is the principal negative regulator of the PI3K pathway.”
- The Glucose Transporter Glut1 is Selectively Essential for CD4 T Cell Activation and Effector Function (2014, neutral): “However, decreased mTORC1 signaling can lead to exacerbated mTORC2 activity (Zeng et al., 2013) that can also promote glycolytic metabolism (Gubser et al.”