Peptides from allergenic lipocalins bind to formyl peptide receptor 3 in human dendritic cells to mediate TH2 immunity

BackgroundHow TH2-mediated allergic immune responses are induced is still under investigation.ObjectiveIn an in vitro system we compared the effect of lipocalin allergens and nonallergenic homologues on human monocyte-derived dendritic cells (DCs) to investigate how they polarize naive CD4+ TH cells. Microarray data gained with these DCs showed a significant difference in expression of formyl peptide receptors (FPRs). Activation of FPR3 in human monocyte-derived DCs leads to inhibition of IL-12 production. Low concentrations of IL-12 during T-cell priming biases immune responses toward TH2. We hypothesize that binding of allergenic lipocalins to FPR3 might be a mechanism for induction of allergic immune responses.MethodsWe examined whether lipocalins and FPR3 colocalize within the cells by using confocal microscopy. With calcium mobilization assays of FPR3-transfected HEK 293 cells, we measured FPR3 signaling in response to allergenic and nonallergenic lipocalins. Silencing of FPR3 in DCs and pretreatment with an antagonistic peptide were used to assess the function of FPR3 in TH2 induction.ResultsFPR3 and lipocalins colocalize in the same vesicles in DCs. Cathepsin S–digested allergenic lipocalins, but not digestion products of nonallergenic homologues, activate FPR3 signaling. FPR3 silencing in DCs or pretreatment with an antagonistic peptide restores IL-12 and induces IL-10 expression by DCs treated with lipocalin allergens, attenuating the TH2 bias and inducing IL-10 production in cocultured TH cells.ConclusionWe describe a novel molecular mechanism for induction of TH2-mediated allergic immune responses. How TH2-mediated allergic immune responses are induced is still under investigation. In an in vitro system we compared the effect of lipocalin allergens and nonallergenic homologues on human monocyte-derived dendritic cells (DCs) to investigate how they polarize naive CD4+ TH cells. Microarray data gained with these DCs showed a significant difference in expression of formyl peptide receptors (FPRs). Activation of FPR3 in human monocyte-derived DCs leads to inhibition of IL-12 production. Low concentrations of IL-12 during T-cell priming biases immune responses toward TH2. We hypothesize that binding of allergenic lipocalins to FPR3 might be a mechanism for induction of allergic immune responses. We examined whether lipocalins and FPR3 colocalize within the cells by using confocal microscopy. With calcium mobilization assays of FPR3-transfected HEK 293 cells, we measured FPR3 signaling in response to allergenic and nonallergenic lipocalins. Silencing of FPR3 in DCs and pretreatment with an antagonistic peptide were used to assess the function of FPR3 in TH2 induction. FPR3 and lipocalins colocalize in the same vesicles in DCs. Cathepsin S–digested allergenic lipocalins, but not digestion products of nonallergenic homologues, activate FPR3 signaling. FPR3 silencing in DCs or pretreatment with an antagonistic peptide restores IL-12 and induces IL-10 expression by DCs treated with lipocalin allergens, attenuating the TH2 bias and inducing IL-10 production in cocultured TH cells. We describe a novel molecular mechanism for induction of TH2-mediated allergic immune responses.