A regulatory TRIF/IL-1R1 axis controls T-dependent IgA production in the intestines.

Mucosal IgA is critical for controlling the microbiota and preventing pathogenic infection of the epithelium. The innate signals that regulate the generation of IgA remain poorly defined. Here, we identified TRIF and IL-1R1 as immune checkpoints for intestinal IgA production. In the absence of infection, Trif -/- and Il1r1 -/- mice exhibited markedly elevated stool IgA and IgA-bound commensals. We show that IL-1R1 restricts IgA class-switching in a B cell-intrinsic manner, while TRIF acts extrinsically of B cells and shapes the Peyer's patch microenvironment. Loss of either Trif or Il1r1 enhanced retinoic acid metabolism and allowed premature Ccnd3 upregulation in naive B cells, favoring both IgA class-switching and differentiation into germinal center B cells. During oral vaccination, the absence or blockade of the TRIF/IL-1R1 pathway increased antigen-specific IgA production without affecting seric antigen-specific IgG levels. These findings unveil novel and local signaling targets to promote robust antigen-specific mucosal immunity.