Interferon gamma-induction of TH1-like regulatory T cells controls anti-viral responses

Regulatory T cells (Tregs) are an immunosuppressive population that are required to maintain peripheral tolerance and prevent tissue damage during immunopathology, via anti-inflammatory cytokines, inhibitor receptors and metabolic disruption. We report that Tregs acquire an effector-like state, yet remain stable and functional, when exposed to IFN? during chronic infection with lymphocytic choriomeningitis (LCMV) and Influenza A virus (IAV). Mechanistically, Treg-restricted-deletion of the IFN? receptor 1 (IFNGR1), but not the IL12 receptor, prevented TH1-like polarization (decreased expression of T-bet, CXCR3 and IFN?) and promoted TH2-like polarization (increased expression of GATA-3, CCR4 and IL4). TH1-like Tregs limited CD8+ T cell effector function, proliferation and memory formation during chronic and acute infection. These findings provide fundamental insights into how Tregs sense inflammatory cues from the environment (IFN?) during viral infection to provide immune guidance to the effector T cell response, to prevent prolonged immunoinflammatory responses and shape the quality of the memory response. Overall design: Our goal was to determine how Tregs become specialized in response to inflammation in vivo and the consequential impact on primary and secondary responses to viral infection. We report that viral infection promotes TH1-like differentiation of Tregs in vivo. Since TH1 cells produce IFN?, we asked if IFN? promoted TH1-like polarization in Tregs. Surprisingly, Ddeletion of the IFN? receptor (IFNGR1), but not the IL12 receptor (IL12RB2), from Tregs robustly prevented TH1 polarization and consequently induced TH2 polarization. TH2-like Ifngr1-deficient Tregs were unable to adequately limit the T cell anti-viral response and CD8+ T cell effector memory, and central memory, formation. Our study uncovers a unique mechanism underlaying how Tregs respond to inflammation to program their immunosuppressive function appropriately and limit excessive immunoinflammatory responses.