IL-23 Licenses Pathogenic Th17 Transdifferentiation via STAT4-dependent Upregulation of IL-12Rβ2

Abstract

Th17 cells exhibit substantial developmental plasticity, transdifferentiating into pathogenic, interferon-{gamma} (IFN-{gamma})-producing Th1-like effectors during chronic autoimmune inflammation. While both IL-23 and IL-12 are implicated in this process, how these structurally related cytokines coordinate to drive transdifferentiation remains unresolved. Here, we show that IL-23 acts as a developmental licensor rather than a terminal trigger, priming Th17 cells for transdifferentiation upon subsequent IL-12 encounter. IL-23 signals through STAT4 to upregulate the IL-12-specific receptor subunit IL-12R{beta}2, lowering the signalling threshold for IL-12. This licensing can be conferred at both early and late stages of Th17 development and produces a temporal logic in which IL-23-mediated STAT4 signaling functionally arms Th17 cells to terminally transdifferentiate in response to IL-12. Using Stat4 conditional knockouts and a structure-based IL-23 mutein that selectively abolishes IL-23-driven STAT4 signaling while preserving STAT3-dependent lineage maintenance, we genetically establish the IL-23-STAT4-IL-12R{beta}2 axis as a discrete licensing module. Furthermore, using the adoptive Th17 transfer colitis model, we show that host-derived IL-23 and IL-12 are required for Th17-driven colitis, and the inflamed colonic environment reconstitutes transdifferentiation capacity in classically "non-pathogenic" Th17 cells. These findings reframe the pathogenic dichotomy of Th17 cells as one of cumulative cytokine exposure rather than fixed cellular fate, and reveal a stepwise architecture of Th17 plasticity in which IL-23 licensing and IL-12 triggering operate as functionally distinct events. Significance StatementTh17 cells protect mucosal barriers but can convert into pathogenic, IFN-{gamma}-producing effectors that drive inflammatory bowel disease (IBD). Although IL-23 is essential for this conversion, the underlying molecular mechanism remains elusive. We show that IL-23 does not directly trigger transdifferentiation but instead licenses Th17 cells for this conversion, during both early and late stages of their development. By signaling through STAT4, IL-23 upregulates the IL-12-specific receptor subunit IL-12R{beta}2 on Th17 cells, rendering them responsive to subsequent IL-12 exposure. Our findings reframe the classical "pathogenic" versus "non-pathogenic" Th17 distinction and provide a mechanistic basis for the clinical efficacy of IL-23-targeted therapies in IBD.