Interferon Gamma Induction of TH1-like Tregs Dampens Anti-viral Responses

We have previously shown that T_reg response to interferon gamma (IFNγ) in the tumor microenvironment is required for response to immunotherapy. We aimed to determine the role of T_reg response to IFNγ during viral infection and the impact on suppression of the anti-viral T cell response. Mice, which have IFNγ receptor (IFNGR1) deleted from T_regs (Ifngr1^L/LFoxp3^Cre-YFP) were infected with an acute (Armstrong), or chronic (Clone 13), strain of lymphocytic choriomeningitis virus (LCMV) to study Ifngr1-deficient T_regs compared to controls (Foxp3^Cre-YFP mice). Additionally, mice which have IL12 receptor β2 subunit (IL12Rβ2) deleted from T_regs (Il12b2^L/LFoxp3^Cre-YFP) were infected with Clone 13 to study Il12rb2-deficient T_regs compared to controls. Surprisingly, T_reg response to IFNγ, but not IL12, induced helper T cell 1 (T_H1)-like polarization (expression of T-bet, CXCR3 and IFNγ) in LCMV Clone 13, which was required for adequate suppression of effector T cells. In LCMV Armstrong and Clone 13 infected mice IFNGR1 deletion from T_regs prevented T_H1-like polarization and reverted to a T_H2-like state (expression of GATA-3, CCR4 and IL-4). scRNAseq of viral antigen-specific CD8⁺ T cells from Clone 13 infected mice showed that Ifngr1 deletion from T_regs promoted CD8⁺ T cell memory. These findings were confirmed in an Armstrong/Listeria monocytogenes-GP33 memory model. Further, Ifngr1 deletion from T_regs enhanced response vaccination when challenged with Clone 13. These findings provide fundamental insight on how T_regs sense inflammatory cues from the environment (IFNγ) during chronic viral infection to control the effector T cell response to prevent overt tissue damage, and shape the memory response.