Rig-I essentially stabilizes Tregs' functionality to control immune homeostasis and surveillance

RNA ligand-primed retinoic acid inducible gene I (Rig-I) triggers innate immunity through activating MAVS. However, whether apo-Rig-I also actively regulates immune reactions remains undetermined. Regulatory T cells (Tregs) are critically involved in regulating immune homeostasis and tumor immunosurveillance. Yet, how a potential fragility of Treg function is protected is only partially understood. Here we report that specific ablation of Rig-I in Foxp3+ cells of mouse compromises Tregs' function and induces generation of proinflammatory Ifn?+Foxp3+ Th1-like Tregs especially after TCR signaling, causing overactivation of type I immunity and multi-organ inflammation. Mechanistically, the second CARD of Rig-I, employing differential motif from what mediates association with MAVS, competitively blocks TCR signaling-induced Foxo1 ubiquitination and degradation in Treg effectors. Likewise, this Rig-I-Foxo1 axis responsive to tumorigenic conditions stabilizes Tregs function to establish immunoevasion. Collectively, we demonstrate a genuine activity of apo-Rig-I in maintaining Treg functionality, critically involved in immune homeostasis maintenance and tumor immune-evasion.