It is well documented that dendritic cells (DCs), IntroductionThe differentiation and commitment of T helper (Th) cells to Th1 cells or Th2 cells depends not only on the strength of T-cell receptor and coreceptor signals provided by the direct interaction between T cells and antigen-presenting cells (APCs) but also on cytokine environment produced by the crosstalk between T cells and APCs. [1][2][3] Dendritic cells (DCs) are representative APCs 4,5 and one of the most important DC-derived cytokines for the induction of Th1 cell differentiation is IL-12. [6][7][8][9] The essential roles of IL-12 in both innate and acquired immunity are evidenced by the analysis of IL-12-deficient mice, in which NK-cell responses and Th1-cell differentiation are impaired. 10 In addition to T cells and NK cells, it has been shown that DCs themselves express a high-affinity receptor for IL-12 and can produce considerable amounts of IFN-␥ in response to These observations suggest that DCs are important sources of Th1-promoting cytokines and are thereby involved in the regulation of Th-cell differentiation.The receptor binding of cytokines results in the activation of the Janus family of protein tyrosine kinases (JAKs) and subsequently the activated JAKs phosphorylate signal transducers and activators of transcriptions (STATs). [12][13][14] There are 4 mammalian JAKs: Jak1, Jak2, Jak3, and Tyk2 and they are differentially activated in response to various cytokines. [12][13][14] From the analysis of T cells and NK cells, it has been demonstrated that IL-12 activates Jak2 and Tyk2 and then activates Stat4 that plays pivotal roles in IL-12-induced gene expression. 12-14 Analyses of Stat4-deficient (Stat4 Ϫ/Ϫ ) mice have shown that Stat4 is required for IL-12-dependent IFN-␥ production in T cells and NK cells. 15,16 Tyk2 has originally been identified as an essential molecule for mediating IFN-␣/␤ signaling 17 and subsequently has been shown to be activated in response to 18 19 [21][22][23] To address the specific and nonredundant role of Tyk2, Tyk2-deficient (Tyk2 Ϫ/Ϫ ) mice were generated, and using Tyk2 Ϫ/Ϫ mice, it has been demonstrated that Tyk2 is not essential for many of the biologic responses upon IFN-␣/␤, IL-6, and IL-10 stimulation. 23,24 In contrast, Tyk2 is required for IL-12-induced IFN-␥ production in activated T cells. 23,24 However, the role of Tyk2 in DC functions including the cytokine production and the induction of T helper cell differentiation is still largely unknown.In this study, we show that Tyk2 expression is required for IL-12, IL-23, and IFN-␥ production from DCs upon activation. We also show that Tyk2 expression in DCs is vital for the induction of antigen-specific Th1 cell differentiation. Our results indicate that Tyk2 expression in DCs is involved in the production of Th1-promoting cytokines upon activation and thereby in the induction of Th1-cell differentiation. Materials and methodsAll experiments were performed according to the guidelines of Chiba University, Chiba, Japan. MiceTyk2-deficient (Tyk2 Ϫ...

IL-4 plays a key role in inducing IL-4 production in CD4+ T cells, functioning as an important determinant for Th2 cell differentiation. We show here that IL-4 induces IFN-γ production in B220+ 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 Ab 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 oligodeoxynucleotide-induced IFN-γ production, but not CpG oligodeoxynucleotide-induced IL-12 or IFN-α 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.