MiR-155 is overexpressed in patients with atopic dermatitis and modulates T-cell proliferative responses by targeting cytotoxic T lymphocyte–associated.

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MiR-155 is overexpressed in patients with atopic dermatitis and modulates T-cell proliferative responses by targeting cytotoxic T lymphocyte–associated antigen 4 Enikö Sonkoly, MD, PhD, Peter Janson, PhD, Marja-Leena Majuri, Terhi Savinko, Nanna Fyhrquist, Liv Eidsmo, MD, PhD, Ning Xu, PhD, Florian Meisgen, Tianling Wei, MD, Maria Bradley, MD, PhD, Jan Stenvang, PhD, Sakari Kauppinen, PhD, Harri Alenius, PhD, Antti Lauerma, MD, PhD, Bernhard Homey, MD, PhD, Ola Winqvist, MD, PhD, Mona Ståhle, MD, PhD, Andor Pivarcsi, PhD Journal of Allergy and Clinical Immunology Volume 126, Issue 3, Pages 581-589.e20 (September 2010) DOI: 10.1016/j.jaci.2010.05.045 Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 miRNA expression differentiates atopic dermatitis from healthy skin. A, Heat map of miRNA TaqMan array data of skin from healthy subjects (H) and lesional skin from patients with atopic dermatitis (AD). B, Scatter plot of differential miRNA expression according to the significance analysis of microarrays algorithm (upregulated in red and downregulated in green). C, Quantitative real-time PCR analysis of miR-155 in healthy (n = 29) and atopic dermatitis lesional (n = 18) skin. ∗∗∗P < .001. Journal of Allergy and Clinical Immunology 2010 126, 581-589.e20DOI: (10.1016/j.jaci.2010.05.045) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Expression of miR-155 in atopic dermatitis skin. A, Flow cytometric analysis of single-cell suspensions from atopic dermatitis skin. B, Numbers of sorted cell populations (left), miR-155 expression as determined by means of quantitative PCR in the sorted cell populations (middle), and estimated contribution of cell populations to total miR-155 (miR-155 expression × number of sorted cells, right). Bars show representative data obtained with cells sorted from one of 3 atopic dermatitis biopsy specimens. C, miR-155 (red) and CD4 (green) expression and 4′-6-diamidino-2-phenylindole dihydrochloride (blue) staining in healthy and atopic dermatitis lesional skin as detected by means of in situ hybridization and immunofluorescence, respectively (original magnification ×400). Journal of Allergy and Clinical Immunology 2010 126, 581-589.e20DOI: (10.1016/j.jaci.2010.05.045) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 Regulation of miR-155 expression in vitro. A, miR-155 expression in naive T cells, TH1 cells, TH2 cells, and regulatory T (Treg) cells. After stimulation with anti-CD3 and anti-CD28 antibodies, miR-155 levels were quantified on day 3 (pre-mature) and day 7 (mature), as well as in cells restimulated on day 7 with anti-CD3 and anti-CD28 for 24 hours (activated). miR-155 expression was determined by means of quantitative PCR. B, TH1 and TH2 polarization verified by means of IL-5 and IFN-γ ELISA. C, miR-155 expression in PBMCs isolated from healthy donors or patients with atopic dermatitis treated with IL-2, SEB, ConA, or anti-CD3. ∗P < .05, ∗∗P < .01, ∗∗∗P < .001. Journal of Allergy and Clinical Immunology 2010 126, 581-589.e20DOI: (10.1016/j.jaci.2010.05.045) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 Regulation of miR-155 expression in vivo. A, Nonlesional skin of patients with atopic dermatitis (n = 9) was subjected to patch testing with SEB for 0, 2, 6, and 24 hours. B, Nonlesional skin of patients with atopic dermatitis with a history of house dust mite allergy (n = 10) was subjected to atopy patch testing for 0, 2, 6, and 48 hours. miR-155 expression was analyzed by means of quantitative real-time PCR. ∗∗∗P < .001. Journal of Allergy and Clinical Immunology 2010 126, 581-589.e20DOI: (10.1016/j.jaci.2010.05.045) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 miR-155 targets CTLA-4 for translational suppression. A, Seed match and sequence alignment of CTLA-4 3′-UTR and miR-155. Gray boxes indicate evolutionary conservation of miR-155 target site. The black rectangle indicates positions of nucleotide mismatches introduced to the miR-155 binding site. B, 3′-UTR luciferase reporter assay with wild-type (WT) or mutated CTLA-4 3′-UTR or no 3′-UTR (empty vector) cotransfected with miR-155 precursor or nontargeting miRNA (control). Relative luciferase activity for 5 separate transfections is shown. C, Intracellular CTLA-4 protein levels in stimulated naive CD4+ cells, as measured by means of flow cytometry, after transfection with miR-155 precursor or control precursor. ∗∗P < .01. n.s., Not significant. Journal of Allergy and Clinical Immunology 2010 126, 581-589.e20DOI: (10.1016/j.jaci.2010.05.045) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 6 miR-155 regulates proliferation of T cells. T-cell proliferation measured by means of incorporation of tritiated thymidine after transfection of naive TH cells with either miR-155 precursor, control precursor, or without precursor molecule. Proliferation was measured at days 2 to 3 after restimulation with anti-CD28 antibody and recombinant B7-1/Fc chimera protein. Shown are results from experiments performed on naive CD4+ cells isolated from 4 separate donors. Journal of Allergy and Clinical Immunology 2010 126, 581-589.e20DOI: (10.1016/j.jaci.2010.05.045) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Expression of miR-155 in human organs and cell types in vitro Expression of miR-155 in human organs and cell types in vitro. The expression of miR-155 was analyzed by using quantitative real-time PCR in 20 healthy organs and tissues (each a pool of 3 donors), in healthy skin (n = 29), and in lesional atopic dermatitis skin (n = 18; A), as well as in the cellular constituents of the human skin (B). Error bars represent SEMs. Data are expressed in relative units compared with U48 RNA. MDDCs, Monocyte-derived dendritic cells. Journal of Allergy and Clinical Immunology 2010 126, 581-589.e20DOI: (10.1016/j.jaci.2010.05.045) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Abundance of CD3+, CD86+, and CD20+ cells in atopic dermatitis skin lesions. Immunohistochemical detection of CD3+ cells (T cells; A), CD86+ cells (dendritic cells/macrophages; B), and CD20+ cells (B cells; C) in atopic dermatitis lesional skin. D, Number of cells with a positive staining per view field. Bars represent means + SDs of 9 view fields. Journal of Allergy and Clinical Immunology 2010 126, 581-589.e20DOI: (10.1016/j.jaci.2010.05.045) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Phenotyping in cell suspensions from atopic dermatitis (AD) skin Phenotyping in cell suspensions from atopic dermatitis (AD) skin. Gating was set on PBMCs, and live CD45+ cells were analyzed in cell suspensions from 4 biopsy specimens from atopic dermatitis lesional skin (A and B). CD20 staining was analyzed in 1 patient with atopic dermatitis by means of FACS. A, Representative dot plots of CD4+CD3+ cells. B, Representative dot plots of CD11c+HLA-DR+ cells. C, CD20–HLA-DR staining in PBMCs and atopic dermatitis lesional skin. Journal of Allergy and Clinical Immunology 2010 126, 581-589.e20DOI: (10.1016/j.jaci.2010.05.045) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions