Mechanisms underlying IL-4-induced IFN-γ production in plasmacytoid dendritic cells

细胞因子环境对免疫细胞的分化和承诺至关重要。例如，代表性的Th2细胞因子IL-4诱导Th2细胞进一步分化，而Th1细胞因子IFN-γ与IL-12协同诱导Th1细胞分化。虽然这些正反馈机制对于T辅助细胞的深度分化至关重要，但免疫系统也有许多内在和外在的机制来对抗免疫细胞的过度分化。在这项研究中，我们发现IL-4诱导B22O^+浆细胞样树突状细胞（PDCs）产生IFN-γ。通过寻找在IL-4刺激下产生IFN-γ的细胞群，我们发现在野生型和rag2 ^<-/->脾细胞中，PDCs是IL-4刺激下产生IFN-γ的主要细胞。孤立的PDCs，而不是CD11b^+ dc或CD8^+ dc，在IL-4刺激下产生IFN-γ。在体内，抗ly6g /C抗体消耗PDCs可阻止IL-4诱导的IFN-γ产生。我们还发现IL-4诱导了PDCs中IFN-γ的产生，而不是IL-12或IFN-α的产生，并且也强烈增强了CpG odn诱导的IFN-γ的产生，而不是CpG odn诱导的IL-12或IFN-a的产生。然而，IL-4不诱导Stat6^<-/->PDCs产生IFN-γ。此外，IL-4通过stat6依赖机制诱导PDCs中Stat4的表达，并且只有表达Stat4的PDCs产生IFN-γ。此外，IL-4不诱导Stat4^<-/->PDCs产生IFN-γ。这些结果表明，PDCs通过Stat6-和stat4依赖机制在IL-4刺激下优先产生IFN-γ。

Cytokine environment is critical for the differentiation and commitment of immune cells. For example, IL-4, a representative Th2 cytokine, induces further Th2 cell differentiation, whereas a Th1 cytokine IFN-γ in coordination with IL-12 induces Th1 cell differentiation. While these positive-feedback mechanisms are essential for the profound differentiation of T helper cells, the immune system also has a number of intrinsic and extrinsic machinery to antagonize the excessive differentiation of immune cells.We show in this research that IL-4 induces IFN-γ production in B22O^+ plasmacytoid dendritic cells (PDCs). By searching for cell populations that produce IFN-γ upon IL-4 stimulation, we found that PDCs were a major IFN-γ-producing cell upon IL-4 stimulation in wild-type and Rag-2^<-/-> splenocytes. Isolated PDCs, but not CD11b^+ DCs or CD8^+ DCs, produced IFN-γ upon IL-4 stimulation. In vivo, the depletion of PDCs by anti-Ly6G/C antibody prevented IFN-γ production induced by IL-4 administration. We also found that IL-4 induced IFN-γ production, but not IL-12 or IFN-α production, in PDCs and also strongly enhanced CpG ODN-induced IFN-γ production, but not CpG ODN-induced IL-12 or IFN-a production. However, IL-4 did not induce IFN-γ production in Stat6^<-/->PDCs. Moreover, IL-4 induced Stat4 expression in PDCs through a Stat6-dependent mechanism and only the Stat4-expressing PDCs produced IFN-γ. Furthermore, IL-4 did not induce IFN-γ production in Stat4^<-/->PDCs. These results indicate that PDCs preferentially produce IFN-γ upon IL-4 stimulation by Stat6- and Stat4-dependent mechanisms.