IL-12R signaling promotes type 1 regulatory T cell specialization by sustaining T-bet

Elucidating how regulatory T (Treg) cells specialize and acquire specific suppressive capacities is key for understanding immune regulation in autoimmunity and cancer. Although IL-12 is a key driver of Th1 differentiation, its role in Treg cells remains poorly defined. Here, we investigated whether IL-12R signaling contributes to Treg cell specialization during Th1 immune responses. We show that IL-12R{beta}2 KO Treg cells display reduced type 1 specialization following LCMV infection, resulting in impaired suppressive capacity. Mechanistically, IFN-{gamma} induces a first peak of T-bet, whereas IL-12 acts downstream to sustain T-bet through a positive feedback loop. The decreased suppressive function of IL-12R{beta}2 KO Treg cells alters effector T cell responses during both acute and chronic infections. Importantly, human Treg cells also respond to IL-12, promoting enhanced type 1 specialization. Together, these findings establish IL-12 as a critical regulator of type 1 Treg specialization and highlight the therapeutic potential of targeting this pathway. TeaserIL-12R signaling in Treg cells enables sustained T-bet expression, programing type 1 Tregs for suppression of Th1 responses.