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Blood, 15 July 2007, Vol. 110, No. 2, pp. 553-560.
Prepublished online as a Blood First Edition Paper on March 29, 2007; DOI 10.1182/blood-2006-11-059246.
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IMMUNOBIOLOGY
Expression of Tyk2 in dendritic cells is required for IL-12, IL-23, and IFN- production and the induction of Th1 cell differentiation
Naoki Tokumasa1,
Akira Suto2,
Shin-ichiro Kagami2,
Shunsuke Furuta1,
Koichi Hirose1,
Norihiko Watanabe1,
Yasushi Saito1,
Kazuya Shimoda3,
Itsuo Iwamoto4, and
Hiroshi Nakajima2
1 Department of Allergy and Clinical Immunology, Clinical Cell Biology,
2 Department of Molecular Genetics, Graduate School of Medicine, Chiba University, Japan;
3 Gastroenterology and Hematology, Faculty of Medicine, University of Miyazaki, Japan;
4 Research Center for Allergy and Clinical Immunology, Asahi General Hospital, Chiba, Japan
It is well documented that dendritic cells (DCs), representative antigen-presenting cells, are important sources of Th1-promoting cytokines and are actively involved in the regulation of T-helper–cell differentiation. However, the intracellular event that regulates this process is still largely unknown. In this study, we examined the role of Tyk2, a JAK kinase that is involved in the signaling pathway under IL-12 and IL-23, in DC functions. While the differentiation and maturation of DCs was normal in Tyk2-deficient (Tyk2–/–) mice, IL-12–induced Stat4 phosphorylation was diminished in Tyk2–/– DCs. IL-12–induced IFN- production was also significantly diminished in Tyk2–/– DCs to levels similar to those in Stat4–/– DCs. Interestingly, Tyk2–/– DCs were defective in IL-12 and IL-23 production upon stimulation with CpG ODN. Furthermore, Tyk2–/– DCs were impaired in their ability to induce Th1-cell differentiation but not Th2-cell differentiation. Taken together, these results indicate that the expression of Tyk2 in DCs is crucial for the production of Th1-promoting cytokines such as IL-12 and IFN- from DCs and thereby for the induction of antigen-specific Th1-cell differentiation.
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