IRF2 deletion in regulatory T cells enhances anti-viral and anti-tumor immune responses 2257347

Abstract

Abstract Introduction T regulatory cells (Tregs) are vital to limit immunopathology, yet they can also be an immune deterrent during chronic infections and cancer. Interferon Regulatory Factor 2 (IRF2) is a transcription factor that negatively regulates type I interferon (IFN-I) signaling. In response to viral infections, Tregs integrate IFN-I signals to limit their activity and enable antiviral immunity. Methods To understand how IRF2 alters Treg activity during chronic infections, we generated mice with Treg-specific conditional knockout (cKO) of IRF2 and infected them with chronic lymphocytic choriomeningitis virus (LCMV). Mouse melanoma models were used to study role in cancer. Results After infection, Treg numbers were almost entirely abolished in cKO mice, and the few remaining Tregs exhibited high IFN-I signaling and an activated phenotype. Lack of IRF2 expression by Tregs reduced CD8 T precursor exhausted (Tpex) cells and increased the amount and functional activity of effector virus-specific CD8 T cells. cKO mice also had more functional virus-specific CD4 T cells with a skew toward Th1 differentiation during chronic infection. Consistent with the diminished CD8 T cell exhaustion programming in chronic LCMV infection, ∼50% of cKO mice died within the first 2 weeks of infection, while the surviving mice exhibited decreased virus titers and accelerated control of the chronic infection. In response to melanoma, IRF2-deficiency in Tregs enabled better tumor control and substantially extended overall survival. Conclusion Thus, IRF2-serves as a key checkpoint in Tregs to balance IFN-I signaling, with important implications toward immune mediated control of chronic infections and cancer. Funding Source n/a Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)