Dock2 Deficiency Exacerbates Colitis by Impairing Akkermansia muciniphila Colonization via the IL-22–Reg3 Antimicrobial Axis Suppressed by Type 1 T Cell Responses

ABSTRACT: Dedicator of cytokinesis 2 (Dock2), a guanine nucleotide exchange factor that activates the small GTPase Rac1, plays a crucial role in host defense and cytoskeletal regulation. While Dock2 is predominantly expressed in intestinal T cells and is significantly upregulated in patients with inflammatory bowel diseases (IBD), its precise role in intestinal inflammation remains obscure. In this study, we demonstrate that systemic Dock2-deficient mice and T cell-specific Dock2 conditional knockout (Dock2-cKO) mice exhibit exacerbated chemically induced colitis compared to wild-type (WT) controls. Dock2 deficiency led to a substantial reduction in both total and IFN-γ-producing CD8+ T cells, accompanied by elevated colonic IL-22 levels, increased expression of Reg3γ and Reg3β antimicrobial peptides (AMPs), and diminished colonization by Verrucomicrobia, particularly Akkermansia muciniphila (A. muciniphila), at steady state. The expression of Reg3γ&β was suppressed in IL-22- and RORγt-deficient mice, and these AMPs exhibited antimicrobial activity against the expansion and intestinal colonization of A. muciniphila. Co-housing Dock2-cKO mice with WT mice or reintroducing A. muciniphila restored colitis severity to levels comparable to WT mice. The inhibitor against Dock2-Rac1 signaling significantly impaired IFN-γ production in both murine and human T cells. Furthermore, IFN-γ suppressed IL-22 expression induced by IL-1, likely via aryl hydrocarbon receptor (Ahr)-dependent but RORγt-independent mechanisms. Collectively, these findings reveal a critical Dock2-mediated axis linking T cell type 1 responses, IL-22–Reg3 AMPs, and commensal microbiota, particularly A. muciniphila. Targeting Dock2 and its downstream pathways may offer novel therapeutic strategies for IBD and other mucosal-associated immune disorders.

ORGANISM(S): Mus musculus

PROVIDER: GSE288392 | GEO | 2026/06/10

REPOSITORIES: GEO