mTORC1 couples immune signals and metabolic programming to establish T^sub 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^sup 1^. The activation of mTOR, which is the catalytic subunit of the mTORCl and mTORC2 complexes, delivers an obligatory signal for the proper activation and differentiation of effector CD4^sup +^ T cells^sup 2,3^, whereas in the regulatory T-cell (T^sub reg^) compartment, the Akt-mTOR axis is widely acknowledged as a crucial negative regulator of T^sub reg^-cell de novo differentiation^sup 4-8^ and population expansion^sup 9^. However, whether mTOR signalling affects the homeostasis and function of T^sub reg^ cells remains largely unexplored. Here we show that mTORCl signalling is a pivotal positive determinant of T^sub reg^-cell function in mice. Treg cells have elevated steady-state mTORCl activity compared to naive T cells. Signals through the T-cell antigen receptor (TCR) and interleukin-2 (IL-2) provide major inputs for mTORCl activation, which in turn programs the suppressive function of T^sub reg^ cells. Disruption of mTORCl through T^sub reg^-specific deletion of the essential component raptor leads to a profound loss of T^sub reg^-cell suppressive activity in vivo and the development of a fatal early onset inflammatory disorder. Mechanistically, raptor/mTORCl signalling in T^sub reg^ cells promotes cholesterol and lipid metabolism, with the mevalonate pathway particularly important for coordinating T^sub reg^-cell proliferation and upregulation of the suppressive molecules CTLA4 and ICOS to establish T^sub reg^-cell functional competency. By contrast, mTORCl does not directly affect the expression of Foxp3 or anti- and pro-inflammatory cytokines in T^sub reg^ cells, suggesting a non-conventional mechanism for T^sub reg^-cell functional regulation. Finally, we provide evidence that mTORCl maintains T^sub reg^-cell function partly through inhibiting the mTORC2 pathway. Our results demonstrate that mTORCl acts as a fundamental 'rheostat' in T^sub 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^sub reg^-cell suppressive activity in immune homeostasis and tolerance. [PUBLICATION ABSTRACT]