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mTORC1 couples immune signals and metabolic programming to establish Treg-cell function


The mechanistic target of rapamycin (mTOR) pathway integrates diverse environmental inputs, including immune signals and metabolic cues, to direct T-cell fate decisions1. 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 cells2,3, 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 differentiation4,5,6,7,8 and population expansion9. 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.

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Figure 1: mTORC1 signalling is constitutively active in Treg cells and its disruption results in a fatal early onset inflammatory disorder.
Figure 2: Raptor deletion abrogates Treg-cell suppressive activity.
Figure 3: Raptor coordinates Treg-cell proliferation and effector molecule expression by orchestrating cholesterol/lipid biosynthetic metabolism, especially the mevalonate pathway.
Figure 4: Deletion of Rictor does not alter Treg-cell function but partially rescues inflammation in Foxp3creRptorfl/fl mice.

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Gene Expression Omnibus

Data deposits

The microarray data have been deposited in the Gene Expression Omnibus under accession GSE46693.


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We thank A. Rudensky for Foxp3YFP-Cre mice, D. Green for help with metabolic assays, N. Brydon for animal colony management, Y. Wang for editing of the manuscript, and the St Jude Immunology FACS core facility for cell sorting. This work was supported by the US National Institutes of Health (K01 AR053573, R21 AI094089, R01 AI101407 and R01 NS064599), the Lupus Research Institute, and the American Lebanese Syrian Associated Charities (all to H.C.).

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H.Z. designed and performed experiments, and wrote the manuscript; K.Y. contributed to cellular experiments; C.C. contributed to survival curves and technical support; G.N. performed bioinformatic analyses; P.V. performed histological analysis; H.C. designed experiments, contributed to writing the manuscript, and provided overall direction.

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Correspondence to Hongbo Chi.

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Zeng, H., Yang, K., Cloer, C. et al. mTORC1 couples immune signals and metabolic programming to establish Treg-cell function. Nature 499, 485–490 (2013).

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