mTORC1 integrates immune signals to control Treg metabolic activity and suppressive function.
Major finding: mTORC1 integrates immune signals to control Treg metabolic activity and suppressive function.
Mechanism: mTORC1-induced lipid metabolism promotes Treg-cell proliferation and CTLA4 and ICOS expression.
Impact: This nonconventional mechanism programs Treg function and immune homeostasis.
The immune-suppressive activity of regulatory T cells (Treg) is controlled by transcriptional regulation of forkhead box P3 (FOXP3), but how immune signals such as cytokine stimulation activate Treg function remains unclear. The mTOR pathway is a critical sensor of nutrient availability and immune inputs and has been implicated in the differentiation and activation of T-cell lineages. Zeng and colleagues investigated the role of mTOR in the programming of Treg cells and found that mTOR complex 1 (mTORC1) activity was elevated in Treg cells at steady-state and in response to T-cell receptor and interleukin-2 stimulation, which was associated with expression of the Treg effector molecules cytotoxic T-lymphocyte-associated protein 4 (CTLA4) and inducible T-cell co-stimulator (ICOS). Genetic deletion of the mTORC1 protein Raptor specifically in Treg cells did not directly affect FOXP3 or cytokine expression but induced a severe autoimmune disorder, similar to the phenotype in mice lacking Treg cells, and impaired Treg suppressive activity in vivo, suggesting that mTORC1 is necessary to establish Treg function. Consistent with this idea, Raptor deficiency inhibited Treg cell proliferation and decreased expression of CTLA4 and ICOS. The requirement for Raptor/mTORC1 in Treg-cell activation was dependent on mTORC1-mediated regulation of cholesterol and lipid biosynthesis, in particular the mevalonate pathway; inhibition of lipid metabolism via blockade of 3-hydroxy-3-methylglutaryl-CoA reductase, a rate-limiting enzyme in cholesterol synthesis, diminished Treg cell proliferation and prevented effector molecule expression, whereas treatment with mevalonate rescued Treg suppressive function. In contrast, loss of mTORC2 activity, which was not essential for Treg function, partially restored the defect in Treg suppressive activity in the absence of mTORC1, suggesting that mTORC1 also coordinates Treg activity via negative regulation of mTORC2. These results identify mTORC1 as a rheostat that integrates immune signals to program Treg-cell metabolism and suppressive activity.