Novel Bregs down-regulate TLR9-induced cytokine responses in sheep Peyerʹs patches

Regulation of TLR responses is required in the intestine to prevent unnecessary responses to commensal microorganisms and maintain tissue homeostasis. Several mechanisms have been proposed for the regulation of TLR responses in intestinal epithelial and lamina propria cells. However, whether this regulation occurs in Peyerʹs patches (PP) is not known. While investigating cellular responses to the TLR9 agonist CpG ODN, we observed that PP cells responded poorly to CpG ODN stimulation despite expressing TLR9. We hypothesized that PP cells produced the immunoregulatory cytokine IL-10 which suppressed TLR-induced cytokine responses. In vitro neutralization of IL-10 or depletion of CD21+ B cells from PP resulted in significant increases in IL-12, IFNγ and IFNα responses in PP cells stimulated with CpG ODN. Essentially, our investigation have identified a novel population of IL-10-secreting B cells in PP with regulatory functions (Bregs). These Bregs may play an important role in the maintenance of intestinal homeostasis.