Gut dysbiosis promotes the breakdown of oral tolerance mediated through dysfunction of mucosal dendritic cells.

While dysbiosis in the gut is implicated in the impaired induction of oral tolerance generated in mesenteric lymph nodes (MesLNs), how dysbiosis affects this process remains unclear. Here, we describe that antibiotic-driven gut dysbiosis causes the dysfunction of CD11cCD103 conventional dendritic cells (cDCs) in MesLNs, preventing the establishment of oral tolerance. Deficiency of CD11cCD103 cDCs abrogates the generation of regulatory T cells in MesLNs to establish oral tolerance. Antibiotic treatment triggers the intestinal dysbiosis linked to the impaired generation of colony-stimulating factor 2 (Csf2)-producing group 3 innate lymphoid cells (ILC3s) for regulating the tolerogenesis of CD11cCD103 cDCs and the reduced expression of tumor necrosis factor (TNF)-like ligand 1A (TL1A) on CD11cCD103 cDCs for generating Csf2-producing ILC3s. Thus, antibiotic-driven intestinal dysbiosis leads to the breakdown of crosstalk between CD11cCD103 cDCs and ILC3s for maintaining the tolerogenesis of CD11cCD103 cDCs in MesLNs, responsible for the failed establishment of oral tolerance.