Follicle-associated epithelial tuft cells amplify type 2 mucosal immunity and IgA production.

Peyer's patches (PPs) in the intestinal mucosa coordinate antibody responses to luminal microbes and dietary antigens. The follicle-associated epithelium (FAE) is traditionally recognized by the presence of microfold cells (M cells) that mediate antigen sampling in PPs. By analyzing Gfi1b-eGFP reporter mice and human PP biopsies, we identified tuft cells as an additional, evolutionarily conserved FAE population that regulates mucosal immunity. Using mouse models and intestinal organoids, we demonstrate that M cells and tuft cells are distinct lineages arising from Pou2f3+ progenitors, whose differentiation is reciprocally regulated by RANKL and interleukin-13 (IL-13), respectively. Tuft cell-derived IL-25 activates type 2 innate lymphoid cells (ILC2s) in PPs. Furthermore, IL-13 production by ILC2 enhances immunoglobulin A class switching and antigen-specific immunity. These findings reveal a dual surveillance system in the FAE, where developmentally related epithelial lineages use distinct mechanisms to coordinate mucosal immunity.