IRF2 expression in Tregs limits the antiviral immune response to prevent mortality during chronic infection 3529

Abstract Description T regulatory cells (Tregs) are vital to limit immunopathology, yet they can also be an immune deterrent during chronic infections. We previously showed IRF2 deletion limits and alters the type I interferon (IFN-I)-induced suppressive program, allowing cells to resist exhaustion. In contrast, IFN-I at onset of viral infection diminishes Treg function to establish an antiviral response. To study IRF2 in Tregs during chronic infection, conditional knockout (cKO) mice with Tregs lacking IRF2 expression were infected with chronic LCMV. Strikingly, ∼50% of cKO mice died in the first 2 weeks of infection. Tregs numbers after infection were rapidly and sustainably reduced in cKO mice, and remaining Tregs exhibited higher IFN-I signaling and an activated phenotype. Surviving cKO mice had better viral control and more functional CD8 T cells versus littermate controls. Lack of IRF2 expression by Tregs reduced CD8 T precursor exhausted (Tpex) and increased the effector virus-specific CD8 T cells early in infection. cKO mice also had more functional virus-specific CD4 T cells with a higher Th1 differentiation early and later in infection. Depletion of all Tregs in otherwise WT mice before infection also showed reduction in survival, but later in infection, showing that the rapid death in the cKO mice is not only due to lower Treg numbers. We are now defining the mechanisms of how IRF2 expression in Tregs leads to CD4 and CD8 T cell exhaustion, and prevents mortality in chronic infection. Topic Categories Viral Immunology (VIR)