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A Mouse Model of Vitiligo with Focused Epidermal Depigmentation Requires IFN-γ for Autoreactive CD8+ T-Cell Accumulation in the Skin  John E. Harris,

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Presentation on theme: "A Mouse Model of Vitiligo with Focused Epidermal Depigmentation Requires IFN-γ for Autoreactive CD8+ T-Cell Accumulation in the Skin  John E. Harris,"— Presentation transcript:

1 A Mouse Model of Vitiligo with Focused Epidermal Depigmentation Requires IFN-γ for Autoreactive CD8+ T-Cell Accumulation in the Skin  John E. Harris, Tajie H. Harris, Wolfgang Weninger, E. John Wherry, Christopher A. Hunter, Laurence A. Turka  Journal of Investigative Dermatology  Volume 132, Issue 7, Pages (July 2012) DOI: /jid Copyright © 2012 The Society for Investigative Dermatology, Inc Terms and Conditions

2 Figure 1 Depigmentation targets the epidermis and spares the hair. (a) Within 4–5 weeks after treatment, hosts developed patchy depigmentation (arrows) at visible epidermal surfaces, including the ears, nose, feet, tail, and occasionally on the trunk under the hair (photographed at 7 weeks). (b) Chronic vitiligo resulted in widespread depigmentation of the epidermis but spared the hair (photographed at 18 weeks). (c) Mice with vitiligo were assigned a vitiligo score based on the extent of involvement, and a representative result at 5 weeks is shown (error bars=mean±SEM, n=3 control, n=5 vitiligo). Journal of Investigative Dermatology  , DOI: ( /jid ) Copyright © 2012 The Society for Investigative Dermatology, Inc Terms and Conditions

3 Figure 2 T cells accumulate in the skin during vitiligo. (a) Green fluorescent protein (GFP)-labeled CD8+ T cells were quantified by flow cytometry of ear skin at the indicated times (error bars=mean±SEM, n=3 per time point). Example flow plots of the CD45+ gate are shown. (b) Tail skin from affected mice harvested 5 weeks after transfer (mouse) is shown with affected skin from a vitiligo patient (human), revealing a patchy mononuclear infiltrate at the dermal–epidermal junction and epidermal infiltration (arrows). Normal mouse skin is shown at inset, bars=50μm. (c) Ears were harvested from mice with vitiligo at 5 weeks after induction, and GFP+ T cells were visualized with fluorescent microscopy (arrow). Bars=100μm. Hairs are visible as short, linear yellow structures due to autofluorescence. Journal of Investigative Dermatology  , DOI: ( /jid ) Copyright © 2012 The Society for Investigative Dermatology, Inc Terms and Conditions

4 Figure 3 Depigmentation correlates with loss of melanocytes. Ear skin from affected mice was harvested at the indicated times. Quantitative real-time reverse transcriptase–PCR revealed a quantifiable decrease in tyrosinase, reflecting the progressive loss of melanocytes during disease (error bars=mean±SEM, n=3 per time point). Journal of Investigative Dermatology  , DOI: ( /jid ) Copyright © 2012 The Society for Investigative Dermatology, Inc Terms and Conditions

5 Figure 4 IFN-γ expression is induced in the skin during vitiligo and is produced by autoreactive CD8+ T cells. (a) Quantitative real-time reverse transcriptase–PCR for IFN-γ was performed on ear skin of mice at the indicated times (error bars=mean±SEM, n=3 mice per time point). (b) Single-cell suspensions were isolated from skin-draining lymph nodes 7 weeks after vitiligo induction and either left unstimulated, or stimulated with PMEL peptide or phorbol 12-myristate 13-acetate (PMA) and ionomycin as indicated. Following stimulation, cells were stained for IFN-γ, and flow cytometry revealed IFN-γ expression in transferred melanocyte-specific CD8+ T cells (green fluorescent protein-positive (GFP+)) and endogenous CD8+ T cells (GFP-). Cells shown are gated on the total CD8+ population, and the percentage shown is of either the total GFP- or GFP+ gate. A representative result is shown. Iono, ionomycin. Journal of Investigative Dermatology  , DOI: ( /jid ) Copyright © 2012 The Society for Investigative Dermatology, Inc Terms and Conditions

6 Figure 5 IFN-γ neutralization prevents depigmentation and melanocyte-specific CD8+ T-cell accumulation in the skin. IFN-γ was neutralized through intraperitoneal injection of IFN-γ–neutralizing antibody (500μg) beginning 2 weeks after induction and twice weekly until scored at 5 weeks (error bars=mean±SEM, n=4 control, n=5 vitiligo, n=4 vitiligo+IFN-γ blockade). (a) Vitiligo score is decreased by IFN-γ neutralization. (b, c) The effects of IFN-γ–neutralizing antibody on the total numbers of melanocyte-specific CD8+ T cells in the ear (b) and in skin-draining lymph nodes (c). LN, lymph node. Journal of Investigative Dermatology  , DOI: ( /jid ) Copyright © 2012 The Society for Investigative Dermatology, Inc Terms and Conditions

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