To cite this article: Kamide Y, Utsugi M, Dobashi K, Ono A, Ishizuka T, Hisada T, Koga Y, Uno K, Hamuro J, Mori M. Intracellular glutathione redox status in human dendritic cells regulates IL‐27 production and T‐cell polarization. Allergy 2011; 66: 1183–1192. Background:  Glutathione redox status, changes in intracellular reduced (GSH) or oxidized (GSSG) glutathione, plays a significant role in various aspects of cellular function. In this study, we examined whether intracellular glutathione redox status in human dendritic cells (DCs) regulates the polarization of Th1/Th2 balance. Methods:  Human monocyte‐derived DCs (MD‐DCs) treated with glutathione reduced form ethyl ester (GSH‐OEt) or L‐buthionine‐(S,R)‐sulfoximine (BSO) were stimulated by lipopolysaccharide (LPS), and the levels of polarization cytokines were measured. Next, DCs matured by LPS or thymic stromal lymphopoietin (TSLP) were cocultured with allogeneic CD4+ naive T cells and Th1/Th2 balance was evaluated by cytokine production from the primed T cells. Results:  Monocyte‐derived DCs exposed to GSH‐OEt and BSO had increased and decreased intracellular GSH contents, respectively. Lipopolysaccharide‐induced interleukin (IL)‐27 production was enhanced by GSH‐OEt and suppressed by BSO, but neither GSH‐OEt nor BSO affected the expression of HLA‐DR, CD80, CD83, or CD86. Mature GSH‐OEt‐treated MD‐DCs enhanced interferon (IFN)‐γ production from CD4+ T cells compared with nontreated MD‐DCs, and small interfering RNA (siRNA) against IL‐27 suppressed the effect of GSH‐OEt on IFN‐γ production. Additionally, although human myeloid DCs activated by TSLP (TSLP‐DCs) prime naïve CD4+ T cells to differentiate into Th2 cells, treatment of TSLP‐DCs with GSH‐OEt reduced IL‐13 production and enhanced IFN‐γ production by CD4+ T cells. Interleukin‐27 siRNA attenuated the inhibitory effect of GSH‐OEt on Th2 polarization. Conclusion:  Our results reveal that Th1 and Th2 responses are controlled by intracellular glutathione redox status in DCs through IL‐27 production.