Journal of Allergy and Clinical Immunology

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Journal of Allergy and Clinical Immunology A skewed pool of resident T cells triggers psoriasis-associated tissue responses in never-lesional skin from patients with psoriasis Irène Gallais Sérézal, MD, Elena Hoffer, MSc, Borislav Ignatov, MD, Elisa Martini, PhD, Beatrice Zitti, PhD, Marcus Ehrström, MD, PhD, Liv Eidsmo, MD, PhD Journal of Allergy and Clinical Immunology DOI: 10.1016/j.jaci.2018.08.048 Copyright © 2018 The Authors Terms and Conditions

Journal of Allergy and Clinical Immunology DOI: (10.1016/j.jaci.2018.08.048) Copyright © 2018 The Authors Terms and Conditions

Fig 1 NLP responds to T-cell activation with induction of transcriptional pathways associated with psoriasis pathology. A, Clinical picture depicting sampling strategy of biopsy specimens from NLP. B and C, Epidermis was separated from dermis, and RNA was extracted. Principal component analysis (PCA) of 112 RNA transcripts analyzed by using NanoString technologies is presented (n = 5 per group). Fig 1, C, Illustration of the PCA vectors clustering plaque psoriasis (PP) away from NLP, skin from healthy control subjects (HC), and skin from patients with resolved psoriasis (RP). D, Baseline gene expression in epidermis analyzed by using quantitative PCR. HC, n = 4 to 7; NLP, n = 8; patients with RP, n = 9 to 10; patients with PP, n = 6 to 11. RQ, Relative quantification. E-H, Skin explants were incubated with OKT-3 or IgG2a (1 μg/mL) and analyzed by using NanoString technology after separation of epidermis and dermis (n = 5 per group). Fig 1, F, Gene ontology (GO) pathways visualized with Cytoscape (ClueGO) analyzing differentially expressed genes between OKT-3– and IgG2a-exposed epidermis from NLP. Fig 1, G, Venn diagram depicting genes upregulated at baseline in epidermis from patients with PP versus HC epidermis (orange) and differentially expressed genes between OKT-3– and IgG2a–exposed samples in NLP (blue) and HCs (red) epidermis. Fig 1, H, GO pathways using differentially expressed genes in epidermis from NLP epidermis on OKT-3 stimulation. *P < .05. NS, Not significant. Journal of Allergy and Clinical Immunology DOI: (10.1016/j.jaci.2018.08.048) Copyright © 2018 The Authors Terms and Conditions

Fig 2 IFN-α responses are detected in both epidermis from NLP after T-cell activation and in keratinocytes after IFN-γ exposure. A, Heat map of net changes in RNA counts determined by using NanoString technology in epidermis after OKT-3 treatment in IFN-α– and IFN-γ–induced genes. Healthy control subjects (HC), n = 5; NLP, n = 5; patients with plaque psoriasis (PP), n = 5; biologics, n = 6; UVB, n = 5; psoralen and UVA (PUVA), n = 5. B, MX1 expression in sorted keratinocytes from HCs (n = 6), NLP (n = 4), and patients with PP (n = 7) by using quantitative PCR. C, Left, Gating strategy for pDCs in live CD45+ cells from blood or full-thickness skin. Right, Density of pDCs per square millimeter in skin (n = 4-5 donors). D and E, Confluent primary keratinocytes were exposed to cytokines for 16 hours before RNA extraction and supernatant collection. Data are from 2 experiments. Fig 2, D, MX1 expression in keratinocytes determined by using quantitative PCR. Fig 2, E, Concentration of IFN-α in supernatants. RQ, Relative quantification. F-H, Surface marker and cytokine production profiles of T cells in epidermal cell suspension by using flow cytometry gated on live CD3+ T-cell receptor (TCR) γδ− cells. HC, n = 7 to 10; NLP, n = 6-9; patients with PP, n = 7-9. Fig 2, G, Left, Representative FACS plot; right, density of IFN-γ+ T cells. Fig 2, H, Left, Representative histogram of IFN-γ. Right, Mean fluorescence intensity (MFI) and geometric mean. *P < .05. NS, Not significant. Journal of Allergy and Clinical Immunology DOI: (10.1016/j.jaci.2018.08.048) Copyright © 2018 The Authors Terms and Conditions

Fig 3 Enrichment of CCR6+ and CD103+CD49a− T cells in NLP. A-D data obtained from confocal imaging. A, Visualization of epidermal CD8 cells (red), 4′-6-diamidino-2-phenylindole dihydrochloride (DAPI; blue), and collagen IV (white) by using confocal microscopy. B and C, Assessment of CD8 T cells and epidermal thickness in healthy control subjects (HC; n = 5) and NLP (n = 6). D, Representative pictures of CD49a (green), CD8 (red), DAPI (blue), and collagen IV (white) and dot plots depicting counts of epidermal CD49a−CD8+ T cells by using microscopy. HC, n = 5; NLP, n = 6. E-H, Flow cytometric data of epidermal (EPI) and dermal (DERMIS) cell suspension gated on live CD3+ T-cell receptor (TCR) γδ− cells. HCs, n = 9; NLP, n = 9; patients with plaque psoriasis (PP), n = 7. Fig 3, E, Representative flow cytometric dot plot. Fig 3, F, Cumulative bar charts of T-cell subsets: left, CD8; right, CD4. Fig 3, G, Frequencies of the CD103+CD49a− subset in epidermis. Fig 3, H, Frequencies of CCR6+ cells in epidermis. Medians are presented. *P < .05. NS, Not significant. Journal of Allergy and Clinical Immunology DOI: (10.1016/j.jaci.2018.08.048) Copyright © 2018 The Authors Terms and Conditions

Fig 4 Enhanced IL-17 and IFN-γ production in epidermal CCR6+ T cells from NLP. Intracellular cytokine expression was assessed by using flow cytometry after phorbol 12-myristate 13-acetate and ionomycin stimulation in the presence of brefeldin A on live CD3+ T-cell receptor (TCR) γδ− cells. A, Barnes-Hut t-distributed stochastic neighbor embedding analysis of 13-parameter data were performed on live CD3+ T cells from epidermis from NLP (n = 5) and healthy control subjects (HC; n = 5). B-E, Representative dot plots and frequencies and density of cytokine-expressing CCR6+ T cells in epidermis (n = 6-9 per group). Representative graphs and dot plots are shown of frequencies and densities of CCR6+IL-17+ cells among CD3 T cells in epidermis and dermis (Fig 4, B) and IL-22+ (Fig 4, C), IFN-γ+ (Fig 4, D), and IL-17+IFN-γ+ (Fig 4, E) frequencies among CCR6+ T cells. *P < .05. Journal of Allergy and Clinical Immunology DOI: (10.1016/j.jaci.2018.08.048) Copyright © 2018 The Authors Terms and Conditions

Fig 5 Accentuated epidermal CCL20 expression responses after exposure to fungal products in NLP. A, Schematic of experimental setup. B-D, Confluent primary keratinocytes were exposed to 16 hours of stimulation with cytokines. Fig 5, B and C, DEFB4A/B and CCL20 expression in cytokine-stimulated keratinocytes obtained from skin from healthy control subjects (HC) and NLP. Pooled data from 2 experiments. Fig 5, D, Secreted CCL-20 measured in keratinocyte supernatants with Luminex technology. RQ, Relative quantification. E, CCL20 and DEFB4A/B expression in skin explants after 16 hours of stimulation with mannan from Saccharomyces cerevisiae (SC) and heat-killed Candida albicans (CA; n = 5 for CA and n = 9 to 11 for other groups). *P < .05. NS, Not significant. Journal of Allergy and Clinical Immunology DOI: (10.1016/j.jaci.2018.08.048) Copyright © 2018 The Authors Terms and Conditions

Fig 6 Schematic of resident T cells and tissue-responses in NLP. Keratinocytes from NLP showed accentuated CCL20 response to microbial challenge, leading to accumulation of CCR6+ T cells able to produce disease-driving cytokines IL-17, IL-22, and IFN-γ. In parallel, the increased proportion of IFN-γ–producing T cells creates an IFN-α signal in the skin, further amplifying focal inflammation. DC, Dendritic cells. Journal of Allergy and Clinical Immunology DOI: (10.1016/j.jaci.2018.08.048) Copyright © 2018 The Authors Terms and Conditions

Fig E1 Journal of Allergy and Clinical Immunology DOI: (10.1016/j.jaci.2018.08.048) Copyright © 2018 The Authors Terms and Conditions

Fig E2 Journal of Allergy and Clinical Immunology DOI: (10.1016/j.jaci.2018.08.048) Copyright © 2018 The Authors Terms and Conditions

Fig E3 Journal of Allergy and Clinical Immunology DOI: (10.1016/j.jaci.2018.08.048) Copyright © 2018 The Authors Terms and Conditions

Fig E4 Journal of Allergy and Clinical Immunology DOI: (10.1016/j.jaci.2018.08.048) Copyright © 2018 The Authors Terms and Conditions

Fig E5 Journal of Allergy and Clinical Immunology DOI: (10.1016/j.jaci.2018.08.048) Copyright © 2018 The Authors Terms and Conditions