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Dendritic cells (DCs) are critical in immune responses, linking innate and adaptive immunity. We found here that DC-specific deletion of the transcription factor STAT5 was not critical for development but was required for T helper type 2 (TH2), but not TH1, allergic responses in both the skin and lungs. Loss of STAT5 in DCs led to the inability to respond to thymic stromal lymphopoietin (TSLP). STAT5 was required for TSLP-dependent DC activation, including upregulation of the expression of costimulatory molecules and chemokine production. Furthermore, TH2 responses in mice with DC-specific loss of STAT5 resembled those seen in mice deficient in the receptor for TSLP. Our results show that the TSLP-STAT5 axis in DCs is a critical component for the promotion of type 2 immunity at barrier surfaces.

Thymic stromal lymphopoietin (TSLP) is an epithelial-derived cytokine that has been implicated in the initiation of allergic responses. CD4 T cells and dendritic cells are able to respond to TSLP in vitro; however, there has not been a careful dissection of the spatiotemporal response to TSLP by CD4 T cells in vivo during an allergic response. Previous work has suggested a requirement for TSLP in amplifying Th2 responses during allergen challenge by direct action on CD4 T cells; however, these studies did not determine whether there is an effect of TSLP on CD4 T cells during allergen sensitization. In this study we demonstrate an indirect role for TSLP on CD4 T cells during sensitization and challenge phases of an allergic response. This indirect effect of TSLP on CD4 T cells is due in part to the presence of TSLP exclusively in the allergen-sensitized and -challenged skin, rather than the draining lymph nodes. [ABSTRACT FROM AUTHOR]

Dendritic cells (DCs) are critical in immune responses, linking innate and adaptive immunity. We found here that DC-specific deletion of the transcription factor STAT5 was not critical for development but was required for T helper type 2 (TH2), but not TH1, allergic responses in both the skin and lungs. Loss of STAT5 in DCs led to the inability to respond to thymic stromal lymphopoietin (TSLP). STAT5 was required for TSLP-dependent DC activation, including upregulation of the expression of costimulatory molecules and chemokine production. Furthermore, TH2 responses in mice with DC-specific loss of STAT5 resembled those seen in mice deficient in the receptor for TSLP. Our results show that the TSLP-STAT5 axis in DCs is a critical component for the promotion of type 2 immunity at barrier surfaces. [ABSTRACT FROM AUTHOR]

Thymic stromal lymphopoietin (TSLP) is an IL-7-related cytokine expressed predominantly by barrier epithelial cells. TSLP is a potent activator of several cell types, including myeloid-derived dendritic cells, monocytes/macrophages and mast cells. Recent studies have revealed an important role for TSLP in the initiation and progression of allergic inflammatory diseases. In this review, we will discuss the role of TSLP in atopic diseases, as well as its function in immune homeostasis. [ABSTRACT FROM AUTHOR]

Background: Atopic dermatitis is characterized by scratching and by TH2-dominated immune response to cutaneously introduced antigens. Antigen application to skin mechanically injured by tape stripping results in TH2-dominated skin inflammation. Objective: To examine the effect of tape stripping on the capacity of skin dendritic cells (DCs) to polarize T cells toward a TH2 phenotype. Methods: CD11c+ DCs were isolated from skin of BALB/c or C57BL/6 mice. Fluorescein isothiocyanate (FITC)+ and FITC− DCs were isolated from draining lymph nodes (DLNs) 24 hours after painting the skin with FITC. DCs were assessed for their ability to induce cytokine secretion by ovalbumin-stimulated naive CD4+ T cells from T cell receptor-ovalbumin transgenic DO11.10 mice. Cytokine mRNA levels were examined by quantitative PCR. Results: Dendritic cells isolated from the skin of wild-type, but not thymic stromal lymphopoietin (TSLP) receptor−/− or IL-10−/−, mice 6 hours after tape stripping elicited significantly more IL-4 and IL-13 and significantly less IFN-γ production by CD4+ cells than DCs isolated from unmanipulated skin, and expressed significantly more mRNA for the TH2 skewing molecules IL-10, Jagged1, and Jagged2, but significantly less mRNA for the TH1 skewing cytokine IL-12. CD11c+FITC+ cells isolated from DLNs of shaved and tape stripped skin of wild-type, but not TSLP receptor−/− or IL-10−/−, mice polarized T cells significantly more toward TH2 and expressed significantly more IL-10, Jagged1, and Jagged2 mRNA than CD11c+FITC+ cells isolated from DLNs of shaved skin. Tape stripping significantly increased TSLP levels in the skin, and TSLP was shown to play an essential role in the TH2 polarization of skin DCs by tape stripping. Conclusions: Tape stripping upregulates TSLP levels in the skin, which polarizes skin DCs to elicit a TH2 response via the induction of IL-10. [Copyright &y& Elsevier]