Expression of Tyk2 in dendritic cells is required for IL-12, IL-23, and IFN-γ production and the induction of Th1 cell differentiation

Abstract

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...

Tyk2-Signaling Plays an Important Role in Host Defense against Escherichia coli through IL-23-Induced IL-17 Production by γδ T Cells

“…We further found that Tyk2 is critical for IL-17 production by ␥␦ T cells and protection against E. coli infection in vivo. There have been reports showing involvement of Tyk2 in IL-23-mediated signaling using Tyk2-deficient mice, including an impaired STAT3 phosphorylation of ConAstimulated T cells (13) and an impaired IFN-␥ production of dendritic cells (23). However, to our knowledge, this is the first report demonstrating an importance of Tyk2 in IL-23-mediated signaling for IL-17 production.…”

Involvement of Tyrosine Kinase-2 in Both the IL-12/Th1 and IL-23/Th17 Axes In Vivo

“…One report described that Tyk2-deficient macrophages lack NO production upon stimulation with LPS (42), suggesting the possible involvement of Tyk2 in macrophage functions in vivo. In addition, Tyk2 2/2 dendritic cells were reported to be defective in IL-12 and IL-23 production upon stimulation with CpG oligodeoxynucleotide (43). Thus, dendritic cells/macrophages may also play an important role in the pathogenesis of these diseases, because our results suggested that Tyk2 deficiency may affect both pathogenic IFN-g and IL-17.…”

Tyrosine Kinase 2 Plays Critical Roles in the Pathogenic CD4 T Cell Responses for the Development of Experimental Autoimmune Encephalomyelitis

“…IL-23 and IL-12 commonly use the IL-12R␤1 chain, which is associated with Tyk2, for their receptors (23). In fact, Tyk2 was shown to be involved in IL-23-induced STAT3 phosphorylation of activated T cells (24) and in IFN-␥ production of dendritic cells (25). Furthermore, we recently reported that Tyk2 plays a crucial role in IL-23-induced IL-17A production by ␥␦ T cells (26).…”