mTORC1 couples immune signals and metabolic programming to establish T(reg) cell function

The mechanistic target of rapamycin (mTOR) pathway integrates diverse environmental inputs, including immune signals and metabolic cues, to direct T cell fate decisions(1). Activation of mTOR, comprised of mTORC1 and mTORC2 complexes, delivers an obligatory signal for proper activation and differentiation of effector CD4(+) T cells(2,3), whereas in the regulatory T cell (T(reg)) compartment, the Akt-mTOR axis is widely acknowledged as a crucial negative regulator of T(reg) de novo differentiation(4–8) and population expansion(9). However, whether mTOR signaling affects the homeostasis and function of T(regs) remains largely unexplored. Here we show that mTORC1 signaling is a pivotal positive determinant of T(reg) function. T(regs) have elevated steady-state mTORC1 activity compared to naïve T cells. Signals via T cell receptor (TCR) and IL-2 provide major inputs for mTORC1 activation, which in turn programs suppressive function of T(regs). Disruption of mTORC1 through T(reg)-specific deletion of the essential component Raptor leads to a profound loss of T(reg) suppressive activity in vivo and development of a fatal early-onset inflammatory disorder. Mechanistically, Raptor/mTORC1 signaling in T(regs) promotes cholesterol/lipid metabolism, with the mevalonate pathway particularly important for coordinating T(reg) proliferation and upregulation of suppressive molecules CTLA-4 and ICOS to establish T(reg) functional competency. In contrast, mTORC1 does not directly impact the expression of Foxp3 or anti- and pro-inflammatory cytokines in T(regs), suggesting a non-conventional mechanism for T(reg) functional regulation. Lastly, we provide evidence that mTORC1 maintains T(reg) function partly through inhibiting the mTORC2 pathway. Our results demonstrate that mTORC1 acts as a fundamental ‘rheostat’ in T(regs) 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) suppressive activity in immune homeostasis and tolerance.