Notch2 with retinoic acid license IL-23 expression by intestinal EpCAM⁺ DCIR2⁺ cDC2s in mice

Abstract

Despite the importance of IL-23 in mucosal host defense and disease pathogenesis, the mechanisms regulating the development of IL-23–producing mononuclear phagocytes remain poorly understood. Here, we employed an [Venus]Il23a reporter strain to investigate the developmental identity and functional regulation of IL-23–producing cells. We showed that flagellin stimulation or Citrobacter rodentium infection led to robust induction of IL-23–producing EpCAM⁺ DCIR2⁺ CD103⁻ cDC2s, termed cDC[IL23], which was confined to gut-associated lymphoid tissues, including the mesenteric lymph nodes, cryptopatches, and isolated lymphoid follicles. Furthermore, we demonstrated that Notch2 signaling was crucial for the development of EpCAM⁺ DCIR2⁺ cDC2s, and the combination of Notch2 signaling with retinoic acid signaling controlled their terminal differentiation into cDC[IL23], supporting a two-step model for the development of gut cDC[IL23]. Our findings provide fundamental insights into the developmental pathways and cellular dynamics of IL-23–producing cDC2s at steady state and during pathogen infection.