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

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.