Viral RNA-Unprimed Rig-I Restrains Stat3 Activation in the Modulation of Regulatory T Cell/Th17 Cell Balance

Innate immunity activation by viral RNA-primed retinoid acid inducible gene-I (Rig-I) in CD4⁺ T cells antagonizes TGFβ signaling to suppress the differentiation of regulatory T cells (Tregs). However, how viral RNA-unliganded Rig-I (apo-Rig-I) modulates Treg generation remains unclear. In this article, we show that, in the absence of viral infection, Treg differentiation of Rig-I^-/- CD4⁺ T cells was compromised, in the presence of increased generation of Th17 cells and overactivation of Stat3, a critical regulator tilting the Treg/Th17 cell balance. Mechanistically, apo-Rig-I physically associates with Stat3, thereby inhibiting Jak1's association with Stat3 while facilitating Shp2's association to inhibit p-Stat3 levels. Interestingly, inhibition of Stat3 ameliorates the Treg/Th17 imbalance and the colitis observed in Rig-I^-/- mice. Collectively, these results uncover an independent functional contribution of the apo-Rig-I/Stat3 interaction in the maintenance of Treg/Th17 cell balance.