Contreras-Castillo, E.; Zambrano-Romero, J. D.; Perez-Vazquez, D.; Garcia-Patino, M. G.; Tapia-Urzua, G.; Candelario-Martinez, A.; Ramos-Balderas, J. L.; Licona-Limon, I. I.; Madera-Salcedo, I. K.; Rosetti-Scuitto, F.; Crispin-Acuna, J. C.; Noriega-Lopez, L.; Nava, P.; Recillas-Targa, F.; Kaartinen, V.; Henao-Mejia, J.; Flavell, R.; Limon, P. L.

T regulatory cells are a suppressor population critical to control inflammation and maintain tissue homeostasis. The TGF-{beta} pathway is a fundamental signal for T regulatory cell differentiation, yet the molecular determinants of how TGF-{beta} signals regulate all these processes are not completely understood. TIF1{gamma} was demonstrated to promote a noncanonical TGF-{beta}/Smad pathway in HSC, however the role of TIF1{gamma} in Treg function has been largely ignored. Here we showed that TIF1{gamma} deficient Tregs lose stability and acquire an effector phenotype in the presence of an inflammatory stimuli or upon activation. TIF1{gamma} deficient T regs gain a Th1-like Treg phenotype or become pro-inflammatory exTregs, by losing Foxp3 expression and acquiring IFN{gamma} expression in an autoimmune model. Loss of TIF1{gamma} 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 TIF1{gamma}, 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-{beta} was in part responsible to inhibit the Th1-like bias a Treg has in the absence of TIF1{gamma}, however, the proliferative phenotype observed in these cells was mostly independent of TGF-{beta} signaling. Finally, we identified the beta-catenin pathway as the molecular mechanism driving both TIF1{gamma}-dependent Treg stability and proliferation upon inflammation. Altogether, our data demonstrated that TIF1{gamma} 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.