Expression of Tyk2 in dendritic cells is required for IL-12, IL-23, and IFN-gamma production and the induction of Th1 cell differentiation.
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-gamma 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-gamma from DCs and thereby for the induction of antigen-specific Th1-cell differentiation.
Tokumasa
Naoki
N
Department of Allergy and Clinical Immunology, Clinical Cell Biology, Chiba University, Inohana, Chiba, Japan.
Suto
Akira
A
Kagami
Shin-Ichiro
S
Furuta
Shunsuke
S
Hirose
Koichi
K
Watanabe
Norihiko
N
Saito
Yasushi
Y
Shimoda
Kazuya
K
Iwamoto
Itsuo
I
Nakajima
Hiroshi
H
D000818:Animals; D002454:Cell Differentiation; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology*; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D007371:Interferon-gamma / Q000096:biosynthesis*; D018664:Interleukin-12 / Q000096:biosynthesis* / Q000494:pharmacology; D053759:Interleukin-23 / Q000096:biosynthesis*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D010766:Phosphorylation; D050795:STAT2 Transcription Factor / Q000378:metabolism; D053634:TYK2 Kinase / Q000172:deficiency / Q000235:genetics*; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology*
D053759:Interleukin-23; D050795:STAT2 Transcription Factor; D018664:Interleukin-12; D007371:Interferon-gamma; D053634:TYK2 Kinase; C499356:Tyk2 protein, mouse