TIF1γ regulates stability of T regulatory cells during inflammation [ATAC-seq]

Regulatory T cells are a suppressor population critical to control inflammation and maintain tissue homeostasis. The TGF-β pathway is a fundamental signal for regulatory T cell differentiation, yet the molecular determinants of how TGF-β signals regulate all these processes are not completely understood. TIF1γ promotes a noncanonical TGF-β/Smad pathway in HSC, however the role of TIF1γ in Treg function has been largely ignored. Here we show that TIF1γ deficient Tregs lose stability and acquire an effector phenotype upon an inflammatory stimulus. TIF1γ deficient Tregs gain a Th1-like Treg phenotype or become pro-inflammatory exTregs in an autoimmune model; while in a helminth infection model, Tregs lacking TIF1γ expression acquire a Th2-like phenotype. Loss of Foxp3 in TIF1γ deficient Tregs is cell-intrinsic, increases proliferation and enhances glycolytic capacity upon activation. Upon activation, TIF1g deficient Tregs upregulate a transcriptional profile associated with proliferation, T cell activation and T helper differentiation. Additionally, these cells acquire increased chromatin accessibility motifs for transcriptional regulators such as NFKb and different STATs; strongly suggestive of enhanced responsiveness to inflammatory cues. TIF1γ deficient Tregs show enhanced proliferation regardless TGF-β was present in the media or not; however, the T helper-like bias a Treg has in the absence of TIF1γ, occurs only in the absence of TGF-β signaling. Finally, we identified the beta-catenin pathway as the molecular mechanism driving both TIF1γ-dependent Treg stability and proliferation upon inflammation. Unlike any other previous reports eliminating different TGF-β molecular components in Tregs, deletion of TIF1γ severely impaired Treg function and stability upon inflammation. Altogether, our data demonstrates that TIF1γ is required for the maintenance of a suppressor phenotype and stability of Treg lymphocytes during inflammatory conditions in vivo and represents a new modulatory pathway to manipulate Treg cells for therapeutic purposes.