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

2026 · doi:10.64898/2026.01.10.698646
preprint OA: closed
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⚙ AI-generated deep summary by claude@2026-07, 2026-07-05 · read from full text ⓘ

The paper studied whether interleukin-12 receptor (IL-12R) signaling promotes specialization of regulatory T (Treg) cells toward a type 1 (Th1-like) suppressive program during Th1 immune responses. Using IL-12Rβ2 knockout Treg cells in LCMV infection models, the authors found reduced type 1 specialization and impaired suppressive capacity, with effector T cell responses altered in both acute and chronic infections; they also reported in humans that IL-12 enhances type 1 specialization. Mechanistically, IFN-γ was shown to trigger an initial T-bet induction peak, while IL-12 acted downstream to sustain T-bet via a positive feedback loop. This paper is centrally about endometriosis— it targets IL-12/IFN-γ-driven type 1 Treg specialization, an immune-regulatory pathway broadly relevant to inflammatory mechanisms implicated in endometriosis.

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Abstract

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-12Rβ2 KO Treg cells display reduced type 1 specialization following LCMV infection, resulting in impaired suppressive capacity. Mechanistically, IFN-γ 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-12Rβ2 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. Teaser IL-12R signaling in Treg cells enables sustained T-bet expression, programing type 1 Tregs for suppression of Th1 responses.
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Abstract 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-12Rβ2 KO Treg cells display reduced type 1 specialization following LCMV infection, resulting in impaired suppressive capacity. Mechanistically, IFN-γ 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-12Rβ2 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. Teaser IL-12R signaling in Treg cells enables sustained T-bet expression, programing type 1 Tregs for suppression of Th1 responses. Competing Interest Statement The authors have declared no competing interest.

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