Daiya Ohara, Yusuke Takeuchi, Hitomi Watanabe, Yoonha Lee, Hiroki Mukoyama, Toshiaki Ohteki, Gen Kondoh, Keiji Hirota

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

  • Immunology
  • Immunology and Allergy

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 Il23aVenus 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 cDCIL23, 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 cDCIL23, supporting a two-step model for the development of gut cDCIL23. Our findings provide fundamental insights into the developmental pathways and cellular dynamics of IL-23–producing cDC2s at steady state and during pathogen infection.

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