TIF1γ regulates stability of regulatory T cells during inflammation

Regulatory T (T_reg) cells are essential for controlling inflammation and maintaining tissue homeostasis. Transcriptional intermediary factor 1-γ (TIF1γ) has been implicated in noncanonical TGFβ-Smad signaling in hematopoietic stem cells, but its role in T_reg cell function has not been explored. Here we show that TIF1γ-deficient T_reg cells lose Foxp3 expression and acquire effector phenotypes in a cell-intrinsic manner upon inflammatory challenge. In vivo, TIF1γ-deficient T_reg cells adopt type 1 helper T cell-like or pro-inflammatory ex-T_reg cell states in autoimmune settings and display type 2 helper T cell-like features during helminth infection. These cells exhibit transcriptional programs associated with proliferation, T cell activation and T helper differentiation, along with increased chromatin accessibility at regulatory regions enriched for key transcription factors controlling T cell activation and lineage specification. Mechanistically, T_reg cell instability in the absence of TIF1γ is largely independent of transforming growth factor beta signaling and instead is driven by activation of the β-catenin pathway. TIF1γ-deficient T_reg cells accumulate β-catenin and display enhanced TCF7 activity. Genetic or pharmacological targeting of β-catenin restores T_reg cell stability and function. We identify TIF1γ as a critical regulator of T_reg cell stability that restrains β-catenin-TCF7 signaling, thereby preserving Foxp3 expression and preventing inflammatory reprogramming.