Ndfip1 restricts mTORC1 signalling and glycolysis in regulatory T cells to prevent autoinflammatory disease

Foxp3+T regulatory (Treg) cells suppress immune cell activation and establish normal immune homeostasis. How Tregcells maintain their identity is not completely understood. Here we show that Ndfip1, a coactivator of Nedd4-family E3 ubiquitin ligases, is required for Tregcell stability and function.Ndfip1deletion in Tregcells results in autoinflammatory disease. Ndfip1-deficient Tregcells are highly proliferative and are more likely to lose Foxp3 expression to become IL-4-producing TH2 effector cells. Proteomic analyses indicate altered metabolic signature of Ndfip1-deficient Tregcells and metabolic profiling reveals elevated glycolysis and increased mTORC1 signalling. Ndfip1 restricts Tregcell metabolism and IL-4 production via distinct mechanisms, as IL-4 deficiency does not prevent hyperproliferation or elevated mTORC1 signalling in Ndfip1-deficient Tregcells. Thus, Ndfip1 preserves Treglineage stability and immune homeostasis by preventing the expansion of highly proliferative and metabolically active Tregcells and by preventing pathological secretion of IL-4 from Tregcells.