Abstract
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 (T(reg)) compartment, the Akt-mTOR axis is widely acknowledged as a crucial negative regulator of T(reg)-cell de novo differentiation and population expansion. However, whether mTOR signalling affects the homeostasis and function of T(reg) cells remains largely unexplored. Here we show that mTORC1 signalling is a pivotal positive determinant of T(reg)-cell function in mice. T(reg) 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 T(reg) cells. Disruption of mTORC1 through Treg-specific deletion of the essential component raptor leads to a profound loss of T(reg)-cell suppressive activity in vivo and the development of a fatal early onset inflammatory disorder. Mechanistically, raptor/mTORC1 signalling in T(reg) cells promotes cholesterol and lipid metabolism, with the mevalonate pathway particularly important for coordinating T(reg)-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 T(reg) cells, suggesting a non-conventional mechanism for T(reg)-cell functional regulation. Finally, we provide evidence that mTORC1 maintains T(reg)-cell function partly through inhibiting the mTORC2 pathway. Our results demonstrate that mTORC1 acts as a fundamental 'rheostat' in T(reg) 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 T(reg)-cell suppressive activity in immune homeostasis and tolerance.