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

Foxp3⁺ T regulatory (T_reg) cells suppress immune cell activation and establish normal immune homeostasis. How T_reg cells maintain their identity is not completely understood. Here we show that Ndfip1, a coactivator of Nedd4-family E3 ubiquitin ligases, is required for T_reg cell stability and function. Ndfip1 deletion in T_reg cells results in autoinflammatory disease. Ndfip1-deficient T_reg cells are highly proliferative and are more likely to lose Foxp3 expression to become IL-4-producing T_H2 effector cells. Proteomic analyses indicate altered metabolic signature of Ndfip1-deficient T_reg cells and metabolic profiling reveals elevated glycolysis and increased mTORC1 signalling. Ndfip1 restricts T_reg cell metabolism and IL-4 production via distinct mechanisms, as IL-4 deficiency does not prevent hyperproliferation or elevated mTORC1 signalling in Ndfip1-deficient T_reg cells. Thus, Ndfip1 preserves T_reg lineage stability and immune homeostasis by preventing the expansion of highly proliferative and metabolically active T_reg cells and by preventing pathological secretion of IL-4 from T_reg cells.