DNAM-1 immunoreceptor integrates innate and adaptive immune programs to drive intestinal inflammation

Innate and adaptive immune responses play critical roles in the pathogenesis of inflammatory bowel disease (IBD), yet the molecular pathways integrating these responses remain elusive. Here, we identify DNAM-1 immunoreceptor as a central driver of colitis through distinct, cell type-specific mechanisms. Transcriptomic analyses of human and murine group 3 innate lymphoid cells (ILC3s) revealed DNAM-1 as a conserved IL-23-responsive surface molecule associated with inflammatory cytokine production. In an innate immune-driven anti-CD40 monoclonal antibody (mAb)-induced colitis model, DNAM-1 expressed on ILC3s promoted intestinal inflammation by enhancing IL-22 and GM-CSF production via the integration of the Akt-mTORC1-HIF-1 signaling pathway. Genetic ablation or antibody-mediated blockade of DNAM-1 attenuated inflammatory cytokine production and disease severity. Paradoxically, in T cell-dependent colitis, DNAM-1 expression on dendritic cells, but not on ILC3s or CD4 T cells, exacerbated disease by promoting dendritic cell activation and pathogenic Th1 and Th17 differentiation. Notably, therapeutic blockade of DNAM-1 ameliorated disease in both colitis models and exerted complementary effects when combined with anti-TNF therapy, accompanied by modulation of immune activation programs distinct from those regulated by TNF inhibition. Collectively, these findings establish DNAM-1 as a pivotal regulator of intestinal inflammation bridging innate and adaptive immunity and identify DNAM-1 blockade as a next-generation therapeutic strategy for IBD. Highlight{blacktriangleright} DNAM-1 is an IL-23-responsive receptor conserved in human and mouse ILC3s. {blacktriangleright}DNAM-1 on ILC3s drives innate colitis via Akt-mTORC1-HIF-1 signaling. {blacktriangleright}DNAM-1 on DCs promotes T cell-dependent colitis by inducing Th1/Th17 cells. {blacktriangleright}DNAM-1 blockade targets immune pathways distinct from TNF inhibition. {blacktriangleright}Combined DNAM-1 and TNF blockade shows additive therapeutic efficacy in colitis.