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

Abstract: 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: Splenic Tregs and Tetramer+ CD8+ T cells were harvested from Foxp3Cre-YFP or Ifngr1L/LFoxp3Cre-YFP mice that remained naïve or were infected with lymphocytic choriomeningitis virus (LCMV) Clone 13 (Cl 13) for 16d