Langerhans cells are critical in epicutaneous sensitization with protein antigen via thymic stromal lymphopoietin receptor signaling Saeko Nakajima,

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Presentation transcript:

Langerhans cells are critical in epicutaneous sensitization with protein antigen via thymic stromal lymphopoietin receptor signaling Saeko Nakajima, MD, Botond Z. Igyártó, PhD, Tetsuya Honda, MD, PhD, Gyohei Egawa, MD, PhD, Atsushi Otsuka, MD, PhD, Mariko Hara-Chikuma, PhD, Norihiko Watanabe, MD, PhD, Steven F. Ziegler, PhD, Michio Tomura, PhD, Kayo Inaba, PhD, Yoshiki Miyachi, MD, PhD, Daniel H. Kaplan, MD, PhD, Kenji Kabashima, MD, PhD Journal of Allergy and Clinical Immunology Volume 129, Issue 4, Pages 1048-1055.e6 (April 2012) DOI: 10.1016/j.jaci.2012.01.063 Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 LCs are crucial for epicutaneous sensitization with OVA. A, Total clinical severity scores (left panel) and total histology scores (right panel) of LC–non-depleted (LC+) and LC-depleted (LC−) mice (n = 5 mice per group). B, Serum OVA-specific antibodies as determined by ELISA. OD values for IgE, IgG1, and IgG2a levels were measured at a wavelength of 450 nm. ∗P < .05. Journal of Allergy and Clinical Immunology 2012 129, 1048-1055.e6DOI: (10.1016/j.jaci.2012.01.063) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 LCs are critical for antigen-specific T-cell proliferation. Mice in the presence or absence of LCs (LC+ and LC−, respectively) were treated with OVA and transplanted with CFSE-labeled OT-II T cells (n = 5 mice per group). Skin-draining LNs were analyzed for OVA-specific T-cell proliferation (A and B) and mRNA expression levels for IFN-γ and IL-4 (C). Boxes in (A) demarcate divided cells (left) and undivided cells (right). ∗P < .05. GAPDH, Glyceraldehyde-3-phosphate dehydrogenase; ND, not detected. Journal of Allergy and Clinical Immunology 2012 129, 1048-1055.e6DOI: (10.1016/j.jaci.2012.01.063) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 LCs are essential for IgE production. The serum IgE levels (A) and IgE expression levels (B) on peritoneal mast cells (indicated by MFI) of WT and Langerin-DTA mice on FVB (left panel) and B6 (right panel) backgrounds. Mast cells were also preincubated with IgE (labeled with pre-IgE) in vitro before the measurement of IgE expression (Fig 3, B). Each symbol represents an individual animal. ∗P < .05. MFI, Mean fluorescence intensity. Journal of Allergy and Clinical Immunology 2012 129, 1048-1055.e6DOI: (10.1016/j.jaci.2012.01.063) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 TSLPR on LCs is a responsible target of TSLP upon epicutaneous OVA sensitization. Epidermal cell suspensions from B6 (WT) mice with (sensitized) or without (nonsensitized) epidermal application of OVA were stained with TSLPR antibody. TSLPR expressions of MHC class II+ CD11c+ LCs was analyzed by flow cytometry (left, histogram; right, average ± SD of MFI). n = 3 per group. ∗P < .05. MFI, Mean fluorescence intensity. Journal of Allergy and Clinical Immunology 2012 129, 1048-1055.e6DOI: (10.1016/j.jaci.2012.01.063) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 An essential target of TSLP for IgE induction is TSLPR on LCs. A, B6 (Ly45.2) mice were irradiated and transplanted with BM cells from B6 (Ly45.1) mice. The epidermis and the dermis of BMC mice were separated, and single-cell suspensions were stained and analyzed by flow cytometry. B, Total clinical severity scores (left panel) and histology scores (right panel) of TSLPR+/+ BMC, LC-TSLPR−/− BMC, and TSLPR−/− BMC mice (n = 5 mice per group). C, Serum OVA-specific antibodies as determined by ELISA. OD values for IgE, IgG1, and IgG2a levels were measured at a wavelength of 450 nm. ∗P < .05. Journal of Allergy and Clinical Immunology 2012 129, 1048-1055.e6DOI: (10.1016/j.jaci.2012.01.063) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 6 TSLPR on LCs are vital for TH2 induction. TSLPR+/+ BMC, LC-TSLPR−/− BMC, and TSLPR−/− BMC mice were treated with OVA or saline and transplanted with CFSE-labeled OT-II T cells. Skin-draining LNs were analyzed for OVA-specific T-cell proliferation (A and B) and cytokine mRNA expression levels for IFN-γ and IL-4 (C). Boxes in (A) demarcate divided cells (left) and undivided cells (right). n = 5 mice per group. ∗P < .05. GAPDH, Glyceraldehyde-3-phosphate dehydrogenase; ND, not detected. Journal of Allergy and Clinical Immunology 2012 129, 1048-1055.e6DOI: (10.1016/j.jaci.2012.01.063) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 A, Hematoxylin and eosin staining of the back skin of LC–non-depleted or LC-depleted mice after OVA application 3 times (hematoxylin and eosin, original magnification ×400). Scale bar = 100 μm. B, The histologic findings were scored by inflammation, neutrophil infiltration, mononuclear cell infiltration, edema, and epithelial hyperplasia. Data are presented as means ± SDs (n = 5). Journal of Allergy and Clinical Immunology 2012 129, 1048-1055.e6DOI: (10.1016/j.jaci.2012.01.063) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 Impaired penetration of protein antigen into the dermis. B6 mice were patched with FITC-conjugated OVA on the back skin; 72 hours later, patched skin area was analyzed by immunohistochemistry. FITC-conjugated OVA (green) retained above the TJ was indicated by staining with anti–claudin-1 antibody (red) (left panel). FITC (green) readily penetrated into the dermis (right panel). Blue staining (4′-6-diamidino-2-phenylindole, dihydrochloride) indicates nuclei. Dashed white lines represent the border between the dermis and the epidermis. Scale bars = 100 μm. Journal of Allergy and Clinical Immunology 2012 129, 1048-1055.e6DOI: (10.1016/j.jaci.2012.01.063) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E3 Establishment of BMC mice deficient in TSLPR on LCs (LC-TSLPR−/− BMC). B6 mice and B6-background TSLPR−/− mice were irradiated (IR) and transplanted with BM cells (BMT) from B6 mice or TSLPR−/− mice. Because LCs were radioresistant, when TSLPR−/− mice were reconstituted with BM cells from B6 mice, they were deficient in TSLPR on LCs (LC-TSLPR−/− BMC mice). Journal of Allergy and Clinical Immunology 2012 129, 1048-1055.e6DOI: (10.1016/j.jaci.2012.01.063) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E4 A, Hematoxylin and eosin staining of the back skin of TSLPR+/+, LC-TSLPR−/−, and TSLPR−/− mice after OVA application 3 times (hematoxylin and eosin, original magnification ×400). Scale bar = 100 μm. B, The histologic findings were scored by inflammation, neutrophil infiltration, mononuclear cell infiltration, edema, and epithelial hyperplasia. Data are presented as means ± SDs (n = 5). Journal of Allergy and Clinical Immunology 2012 129, 1048-1055.e6DOI: (10.1016/j.jaci.2012.01.063) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E5 TSLP promotes the expression of OX40L and the production of TH2 chemokines by DCs. A, The expression levels of OX40L, CD80, and CD40 of LCs with (sen+) or without (sen−) OVA sensitization in TSLPR+/+ and TSLPR−/− mice (n = 5 mice per group). Cells were pregated on MHC class II+ CD11c+ LC cells. B and C, BM-derived DCs were incubated with or without recombinant TSLP (rTSLP), and mRNA levels of chemokines—CCL17, CCL22, and CXCL10—were measured by real-time quantitative PCR. ∗P < .05. GAPDH, Glyceraldehyde-3-phosphate dehydrogenase; MFI, mean fluorescence intensity. Journal of Allergy and Clinical Immunology 2012 129, 1048-1055.e6DOI: (10.1016/j.jaci.2012.01.063) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions