Dysbiosis-induced expansion of AXL-positive inflammatory type 3 dendritic cells triggers preclinical autoimmunity

Abstract Conventional dendritic cells (cDCs) are key sentinels at epithelial barriers, regulating immunity to microbial pathogens and commensals while preserving tissue integrity. NOTCH2 deficiency in CD11c-expressing cells ( Notch2 cKO ) disrupts type 2a DC (cDC2a) development, impairs intestinal T H 17 immunity and increases susceptibility to enteropathogenic bacteria. This defect leads to persistent dysbiosis in Notch2 cKO mice, characterized by low-grade inflammation and systemic autoimmune features, including elevated autoantibody titers and renal immune complex deposition. Dysbiosis precedes expansion of highly inflammatory AXL-expressing type 3 DCs (AXL + inf-DC3), promoting chronic inflammation and tertiary lymphoid structures driving adaptive immune responses. Notably, dysbiosis is defined by three dominant pathobionts and is transferable to wild-type mice, recapitulating the autoimmune features observed in Notch2 cKO mice. Here these findings identify a microbiota–DC axis linking intestinal pathobionts to systemic autoimmunity, establishing inflammatory DC3 as the cellular bridge between dysbiosis, chronic inflammation and autoimmune pathogenesis.