Ndfip1 Restricts Mtorc1 Signalling And Glycolysis In Regulatory T Cells To Prevent Autoinflammatory Disease

Foxp(3+) 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(H)2 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.