Scientific Associate Princess Margaret Cancer Ctr., Canada, United States
Disclosure(s):
Heidi Elsaesser: No financial relationships to disclose
Introduction/Rationale: 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.
