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

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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.