TIF1γ regulates stability of T regulatory cells during inflammation

T regulatory cells are a suppressor population critical to control inflammation and maintain tissue homeostasis. The TGF-β pathway is a fundamental signal for T regulatory cell differentiation, yet the molecular determinants of how TGF-β signals regulate all these processes are not completely understood. TIF1γ was demonstrated to promote a noncanonical TGF-β/Smad pathway in HSC, however the role of TIF1γ in Treg function has been largely ignored. Here we showed that TIF1γ deficient Tregs lose stability and acquire an effector phenotype in the presence of an inflammatory stimuli or upon activation. TIF1γ deficient T regs gain a Th1-like Treg phenotype or become pro-inflammatory exTregs, by losing Foxp3 expression and acquiring IFNγ expression in an autoimmune model. Loss of TIF1γ in Tregs was cell-intrinsic and was also accompanied by increased proliferation and enhanced glycolytic capacity upon activation. Additionally, we demonstrated that in the absence of TIF1γ, there was an increased methylation status in the CNS2 enhancer region of the Foxp3 locus, further suggesting increased susceptibility for loss of Foxp3 expression. Mechanistically, TGF-β was in part responsible to inhibit the Th1-like bias a Treg has in the absence of TIF1γ, however, the proliferative phenotype observed in these cells was mostly independent 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. Altogether, our data demonstrated 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.