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

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_H17 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.