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

NOTCH2 deficiency in CD11c-expressing cells (Notch2cKO) disrupts type 2a DC (cDC2a) development, impairs intestinal TH17 immunity, and increases susceptibility to enteropathogenic bacteria. This lead to persistent dysbiosis within our Notch2cKO colony, characterized by low-grade inflammation and systemic autoimmune features, including elevated autoantibody titers and renal immune-complex deposition.

Dysbiosis preceded expansion of highly inflammatory AXL-expressing type 3 DC (AXL+inf-DC3), promoting chronic inflammation and tertiary lymphoid structures driving adaptive immune responses. Notably, dysbiosis was defined by three dominant pathobionts and was transferable to WT mice, recapitulating the autoimmune features observed in Notch2cKO mice. Collectively, 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.