Interleukin-10-secreting Peyer's patch cells are responsible for active suppression in low-dose oral tolerance

We demonstrate the induction of antigen-specific interleukin-10 (IL-10)-sec reting cells in murine Peyer's patches (PPs) after low-dose beta -lactoglob ulin (BLG) feeding. In addition, we show that PP cells can inhibit the T-ce ll proliferative response in vitro as well as T-cell-mediated inflammation in vivo. The active suppression mediated by these regulatory cells was seen only within a narrow range of antigen dosage (feeding), with the most prom inent effect at 5 x 1 mg BLG. On either side of this range, T-helper 1-like cytokine responses were observed when PP cells were stimulated with antige n in vitro. This result correlated with reduced production of regulatory cy tokines as well as reduced activity of bystander suppression. We found that changes in IL-10 production correlated inversely with changes in interfero n-gamma production. Inhibitory effects mediated by CD4(+) PP cells were par tially neutralized by antibodies to IL-10 and transforming growth factor-be ta. Interestingly, the generation of such regulatory cells after low-dose B LG feeding exhibited organ dependence. Among spleen, lymph node and PP cell s derived from orally tolerized mice, PP cells were the most effective in p romoting bystander suppression in the presence of BLG, indicating the signi ficance of PPs as an inductive site for antigen-specific regulatory cells u pon induction of low-dose oral tolerance. Moreover, PP cells from mice fed 5 x 1 mg BLG were shown to suppress a BLG-specific delayed-type hypersensit ivity response induced in footpads, suggesting that IL-10-secreting PP cell s regulate systemic inflammation.