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<p>Dedicator of cytokinesis 2 (DOCK2) is a guanine nucleotide exchange factor upregulated in patients with inflammatory bowel disease (IBD), yet its role in intestinal homeostasis remains obscure. Here, we show that both systemic and T cell–specific Dock2-deficient mice develop exacerbated chemical-induced colitis, characterized by reduced CD8⁺ T cells and impaired IFN-γ production, alongside elevated IL-22 and Reg3γ/β antimicrobial peptides (AMPs), and accompanied with decreased colonization of <i>Akkermansia</i> (<i>A.</i>) <i>muciniphila</i>, a beneficial <i>Verrucomicrobia</i> species. Reg3γ/β expression was diminished in IL-22– and RORγt–deficient mice, and both AMPs inhibited <i>A. muciniphila</i> growth. Co-housing with wild-type mice or <i>A. muciniphila</i> reconstitution rescued colitis severity in Dock2-deficient mice. Pharmacologic inhibition of Dock2-Rac1 signaling suppressed IFN-γ in murine and human T cells. Mechanistically, IFN-γ restricted IL-22 by enhancing H3K27 trimethylation on <i>Ahr</i> promoter and suppressing AHR transcription. These findings identify a Dock2–IFN-γ–IL-22–Reg3 axis that controls commensal microbiota and colitis. Targeting Dock2 signaling may offer new therapeutic opportunities in IBD.</p>

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Dock2 Protects Colitis by Facilitating Akkermansia Colonization via Suppressing IL-22–Reg3 Activity

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月22日

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  • Min Lu,
  • Shaoting Xu,
  • Ying Tan,
  • Jianping Deng,
  • Bingbing Feng,
  • Ding Qiu,
  • Xinying Wang,
  • Haiyang Sun,
  • Kaile Ji,
  • Bowen Zhu,
  • Shixian Hu,
  • Xueting Wu,
  • Minhu Chen,
  • Yoichiro Iwakura,
  • Xinying Wang,
  • Rui Feng,
  • Yangfan Qi,
  • Ce Tang

摘要

Dedicator of cytokinesis 2 (DOCK2) is a guanine nucleotide exchange factor upregulated in patients with inflammatory bowel disease (IBD), yet its role in intestinal homeostasis remains obscure. Here, we show that both systemic and T cell–specific Dock2-deficient mice develop exacerbated chemical-induced colitis, characterized by reduced CD8⁺ T cells and impaired IFN-γ production, alongside elevated IL-22 and Reg3γ/β antimicrobial peptides (AMPs), and accompanied with decreased colonization of Akkermansia (A.) muciniphila, a beneficial Verrucomicrobia species. Reg3γ/β expression was diminished in IL-22– and RORγt–deficient mice, and both AMPs inhibited A. muciniphila growth. Co-housing with wild-type mice or A. muciniphila reconstitution rescued colitis severity in Dock2-deficient mice. Pharmacologic inhibition of Dock2-Rac1 signaling suppressed IFN-γ in murine and human T cells. Mechanistically, IFN-γ restricted IL-22 by enhancing H3K27 trimethylation on Ahr promoter and suppressing AHR transcription. These findings identify a Dock2–IFN-γ–IL-22–Reg3 axis that controls commensal microbiota and colitis. Targeting Dock2 signaling may offer new therapeutic opportunities in IBD.