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Mechanical injury polarizes skin dendritic cells to elicit a TH2 response by inducing cutaneous thymic stromal lymphopoietin expression  Michiko K. Oyoshi,

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Presentation on theme: "Mechanical injury polarizes skin dendritic cells to elicit a TH2 response by inducing cutaneous thymic stromal lymphopoietin expression  Michiko K. Oyoshi,"— Presentation transcript:

1 Mechanical injury polarizes skin dendritic cells to elicit a TH2 response by inducing cutaneous thymic stromal lymphopoietin expression  Michiko K. Oyoshi, PhD, Ryan P. Larson, Steven F. Ziegler, PhD, Raif S. Geha, MD  Journal of Allergy and Clinical Immunology  Volume 126, Issue 5, Pages e5 (November 2010) DOI: /j.jaci Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

2 Fig 1 TH2 polarizing effect of tape stripping on ear skin DCs. A, Fluorescence-activated cell sorting analysis of CD11c expression by cells isolated from unmanipulated (UNM) and tape-stripped (Injury) ear skin. Isotype control in gray. B, Number of CD11c+ cells and their subset composition. C, Polarization of CD4+DO11.10 cells by DCs isolated from unmanipulated (-) and tape-stripped (+) ear skin. D, Proliferation of CD4+DO11.10 cells. Columns and error bars represent means and SEMs (n = 4 per group). ∗∗P < .01; ∗∗∗P < cpm, Counts per minute; Max, maximum; mDCs, myeloid DCs; pDCs, plasmacytoid DCs. Journal of Allergy and Clinical Immunology  , e5DOI: ( /j.jaci ) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

3 Fig 2 Expression of mRNA for cytokines and Notch ligands Jagged1 and Jagged2 by skin DCs. Quantitative PCR analysis of mRNA for cytokines and Notch ligands by DCs isolated from unmanipulated (-) and tape-stripped (+) ear skin. Results are expressed as fold induction compared with DCs from unmanipulated skin. Columns and error bars represent means and SEMs (n = 5 per group). ∗P < .05; ∗∗P < .01; ∗∗∗P < .001. Journal of Allergy and Clinical Immunology  , e5DOI: ( /j.jaci ) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

4 Fig 3 Polarization of T cells by DCs from DLNs of shaved and STS skin. A, Kinetic analysis of CD11c+FITC+ DCs in DLNs of shaved and STS skin painted with FITC. B, Representative fluorescence-activated cell sorting analysis of CD11c+FITC+ DCs in skin DLNs 24 hours after FITC painting. C, Number and subset composition of CD11c+FITC+ cells in DLNs of shaved and STS skin (n = 3). D, Representative FACS analysis of CD40, CD80, CD86, MHC class II, OX40L, and CCR7 expression on FITC+ DCs from DLNs 24 hours after FITC painting. E, Polarization of CD4+DO11.10 cells by CD11c+FITC+ DCs and CD11c+FITC− DCs isolated from DLNs of FITC-painted skin. F, Proliferation of CD4+DO11.10 cells. G, Quantitative PCR analysis of mRNA expression of GATA-3 and T-bet in CD4+DO11.10 cells purified after coculture with DCs and OVAp. Results are expressed as fold induction compared with CD4+ T cells cultured in the absence of DCs. Columns and error bars represent means and SEMs (n = 5 per group). ∗P < .05; ∗∗P < .01; ∗∗∗P < cpm, Counts per minute; LN, lymph node; Max, maximum; mDCs, myeloid DCs; pDCs, plasmacytoid DCs. Journal of Allergy and Clinical Immunology  , e5DOI: ( /j.jaci ) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

5 Fig 4 Expression of mRNA for cytokines and Notch ligands Jagged1 and Jagged2 by DCs from DLNs of shaved and STS skin. CD11c+FITC+ and CD11c+FITC− from DLNs of shaved and STS skin for cytokines and Notch ligands. Results are expressed as fold induction compared with CD11c+FITC− cells from DLNs of shaved skin. Columns and error bars represent means and SEMs (n = 5 per group). ∗P < .05; ∗∗P < .01; ∗∗∗P < .001. Journal of Allergy and Clinical Immunology  , e5DOI: ( /j.jaci ) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

6 Fig 5 TSLP is important for the TH2 polarizing effect of tape stripping on skin DCs. A, TSLP levels in the skin. B, TH-cell polarizing activity of DCs from unmanipulated (-) and tape-stripped (+) skin of TSLPR−/− mice and WT controls. C, Quantitative PCR analysis of mRNA for IL-10 and Notch ligands by ear skin DCs from TSLPR−/− mice and WT controls. Results are expressed as fold induction compared with DCs from unmanipulated skin of WT controls. D, TH-cell polarizing activity of CD11c+FITC+ DCs from DLNs of shaved (Sh) and STS skin of TSLPR−/− mice and WT controls. Columns and error bars represent means and SEMs (n = 4 per group). ∗P < .05; ∗∗P < .01; ∗∗∗P < .001. Journal of Allergy and Clinical Immunology  , e5DOI: ( /j.jaci ) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

7 Fig 6 IL-10 is important for the TH2 polarizing effect of tape stripping on skin DCs. A, Polarization of CD4+DO11.10 cells by DCs isolated from unmanipulated (-) and tape-stripped (+) ear skin of IL-10−/− mice and WT controls. B, Quantitative PCR analysis of mRNA for cytokines and Notch ligands. Results are expressed as fold induction compared with DCs from unmanipulated skin of WT controls. C, Polarization of CD4+DO11.10 cells by CD11c+FITC+ DCs isolated from DLNs of FITC-painted skin of IL-10−/− mice and WT controls. Columns and error bars represent means and SEMs (n = 5 per group). ∗P < .05; ∗∗P < .01; ∗∗∗P < n.d., Not detectable; Sh, shaved. Journal of Allergy and Clinical Immunology  , e5DOI: ( /j.jaci ) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

8 Expression of costimulatory and MHC class II molecules on skin DCs and kinetics of thymidine incorporation by T cells stimulated with antigen presented by skin DCs. A, Representative fluorescence-activated cell sorting analysis of CD40, CD80, CD86, MHC class II, and OX40L expression by CD11c+ cells from unmanipulated (UNM) or tape-stripped ear (Injury) skin. B, Kinetics of thymidine incorporation to cultures of CD4+DO11.10 cells stimulated with OVAp and DCs from UNM or Injury skin. [3H]-thymidine was added at 88 hours of culture, and incorporation was assessed after 8 hours (total, 96 hours culture), 16 hours (total, 104 hours culture), or 24 hours (total, 120 hours culture). cpm, Counts per minute; Max, maximum. Journal of Allergy and Clinical Immunology  , e5DOI: ( /j.jaci ) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

9 Expression of costimulatory and MHC class II molecules on FITC+ versus FITC− DCs from DLNs of FITC-painted shaved and STS skin. Representative fluorescence-activated cell sorting analysis of expression of CD40, CD80, CD86, MHC class II, OX40L, and CCR7 on FITC+ DCs and FITC− DCs from DLNs 24 hours after painting shaved skin (upper panel) and STS skin (lower panel) with FITC. Max, Maximum. Journal of Allergy and Clinical Immunology  , e5DOI: ( /j.jaci ) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

10 Expression of costimulatory and MHC class II molecules on DCs isolated from unmanipulated and tape stripped skin of TSLPR−/− mice and WT controls. Representative FACS analysis of expression of CD40, CD80, CD86, MHC class II, and OX40L on CD11c+ cells isolated from unmanipulated (UNM) and tape-stripped (Injury) ear skin of TSLPR−/− mice and WT controls. Max, Maximum. Journal of Allergy and Clinical Immunology  , e5DOI: ( /j.jaci ) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

11 Quantitative PCR analysis of mRNA for cytokines and Notch ligands by DCs isolated from unmanipulated skin and cultured with (+) or without (-) mouse recombinant TSLP (rTSLP). DCs isolated from unmanipulated BALB/c skin were incubated with medium or 100 ng/mL rTSLP (Peprotech, Rocky Hill, NJ) for 16 hours in RPMI complete medium, and RNA was isolated as described in Methods. Results are expressed as fold induction compared with DCs from unmanipulated skin of WT controls. Journal of Allergy and Clinical Immunology  , e5DOI: ( /j.jaci ) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

12 TH2 polarizing effect of tape stripping on skin DCs in C57BL/6 mice
TH2 polarizing effect of tape stripping on skin DCs in C57BL/6 mice. A, Polarization of CD4+OT-II cells by DCs from unmanipulated (-) and tape-stripped (+) ear skin of C57BL/6 mice. Dendritic cells from tape-stripped skin induced T cells to secrete significantly more IL-4 and IL-13 compared with DCs from unmanipulated skin. Induction of IFN-g secretion was also higher, but the difference was not significant. B, Proliferation of CD4+OT-II cells to OVA peptide. DCs from tape-stripped skin and unmanipulated skin elicited comparable T-cell proliferation. C, Quantitative PCR analysis of mRNA for cytokines and Notch ligands. Results are expressed as fold induction compared with DCs from unmanipulated skin. Dendritic cells from tape-stripped skin of C57BL/6 mice expressed significantly higher levels of IL-10, Jagged1, and Jagged2 mRNA than DCs from unmanipulated skin. In contrast with findings in BALB/c mice, DCs from tape-stripped skin of C57BL6 mice also expressed significantly higher amounts of IL-12 mRNA. D, Polarization of CD4+OT-II cells by CD11c+FITC+ DCs and CD11c+FITC− DCs isolated from DLN of FITC-painted skin of C57BL/6 mice. CD11c1FITC1 cells purified from DLNs of STS skin of C57BL6 mice induced significantly higher secretion of IL-4 and IL-13 than CD11c1FITC1 cells from DLNs of shaved skin but comparable secretion of IFN-g. CD11c1FITC1 cells from DLNs of STS and shaved skin induced significantly higher secretion of TH2 and TH1 cytokines IFN-g compared with their CD11c1FITC- counterparts CD11c1FITC- cells from DLN of STS and shaved skin were comparable in inducing TH2 and TH1 cytokines. E, Proliferation of CD4+OT-II cells. There were no significant differences between any of the CD11c+ subpopulations in supporting T-cell proliferation. Columns and error bars represent means and SEMs (n = 3 per group). ∗P < .05; ∗∗P < .01; ∗∗∗P < cpm, Counts per minute. Journal of Allergy and Clinical Immunology  , e5DOI: ( /j.jaci ) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

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