Human skin dendritic cell fate is differentially regulated by the monocyte identity factor Kruppel-like factor 4 during steady state and inflammation

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Presentation transcript:

Human skin dendritic cell fate is differentially regulated by the monocyte identity factor Kruppel-like factor 4 during steady state and inflammation Jennifer Jurkin, PhD, Corinna Krump, MSc, René Köffel, PhD, Christina Fieber, MSc, Christopher Schuster, MD, Patrick M. Brunner, MD, Izabela Borek, MSc, Gregor Eisenwort, MD, Clarice Lim, BSc(Hon), Jörg Mages, PhD, Roland Lang, MD, Wolfgang Bauer, MD, Diana Mechtcheriakova, PhD, Anastasia Meshcheryakova, MSc, Adelheid Elbe-Bürger, PhD, Georg Stingl, MD, Herbert Strobl, MD Journal of Allergy and Clinical Immunology Volume 139, Issue 6, Pages 1873-1884.e10 (June 2017) DOI: 10.1016/j.jaci.2016.09.018 Copyright © 2016 The Authors Terms and Conditions

Journal of Allergy and Clinical Immunology 2017 139, 1873-1884 Journal of Allergy and Clinical Immunology 2017 139, 1873-1884.e10DOI: (10.1016/j.jaci.2016.09.018) Copyright © 2016 The Authors Terms and Conditions

Fig 1 Identification of transcription factors regulated during LC commitment. A, Sorted CD34+CD45RAlow, CD34+CD45RAint, and CD34+CD45RAhigh progenitor subsets cultured for 7 days under monocyte-promoting (–TGF-β1) or LC-promoting (+TGF-β1) conditions. B, Schematic representation of microarray set-up. C, Quantitative PCR validation of selected transcription factors (n = 4-8, ± SEM). *P < .05, **P < .01, and ***P < .001, t test. Journal of Allergy and Clinical Immunology 2017 139, 1873-1884.e10DOI: (10.1016/j.jaci.2016.09.018) Copyright © 2016 The Authors Terms and Conditions

Fig 2 KLF4 is downregulated during LC differentiation. A, KLF4 expression of CD14+ blood monocytes stimulated with indicated cytokines. B, KLF4 expression of FACS-purified p-LCs or p-moDCs (± IFN-γ). C, FACS and KLF4 expression analysis of day 7 p-moDCs, p-LCs, or progenitor-derived monocytes (p-monocytes). D and E, Lineage marker profile (Fig 2, D) and KLF4 expression (Fig 2, E) of CD1a+ cells of day 7 p-moDC or p-LC cultures. F, FACS and Western blot analysis of day 5 progenitors cultured with or without TGF-β1 for 7 days (n = 3). Journal of Allergy and Clinical Immunology 2017 139, 1873-1884.e10DOI: (10.1016/j.jaci.2016.09.018) Copyright © 2016 The Authors Terms and Conditions

Fig 3 LCs and prenatal LC precursors do not express KLF4. A, LCs and prenatal HLA-DR+ LCs are indicated by arrows, and dermal HLA-DR+ cells are indicated by arrowheads (n = 4 per developmental stage). B, Staining of dermal CD14+ or CD1a+ DCs of adult human skin. C, Grading of KLF4 expression of dDCs (n = 6). D, KLF4 mRNA levels of LCs, monocytes (Mo), CD1a+ dDCs, or CD14+ dDCs and keratinocytes (KC) isolated from healthy adult human skin (n = 3). Journal of Allergy and Clinical Immunology 2017 139, 1873-1884.e10DOI: (10.1016/j.jaci.2016.09.018) Copyright © 2016 The Authors Terms and Conditions

Fig 4 KLF4 is repressed by Notch signaling. A, Sections of healthy human skin (top) and cytospun in vitro–generated p-LCs, moLCs, and moDCs (bottom). B, TGF-β1–dependent upregulation/downregulation of Notch target genes after 6 and 24 hours (n = 3). C, NOTCH1 and JAG2 surface expression of CD34+ progenitors and p-LC generation cultures (n = 4). D, FACS analysis of intracellular active NOTCH1 (aN1) of day 5 moLCs and moDCs and day 7 p-LCs (n = 4). Journal of Allergy and Clinical Immunology 2017 139, 1873-1884.e10DOI: (10.1016/j.jaci.2016.09.018) Copyright © 2016 The Authors Terms and Conditions

Fig 5 Ectopic KLF4 interferes with LC differentiation. A, FACS of GFP+ day 5 progenitors (n = 6). *P < .05 and **P < .01, t test. B, Day 5 progenitors subcultured with TGF-β1 (n = 6). *P < .05 and ***P < .001, t test. C, Schematic representation of experimental set-up for KLF4 induction. D, CD1a/CD207 expression of day 7 GFP+ cells cultured according to Fig 5, C (n = 3). *P < .05, t test. E, FACS of day 5 progenitors subcultured under p-moDC conditions (n = 6). F and G, Cytokine secretion of day 7 GFP+CD1a+CD207+ p-LCs (Fig 5, F) or GFP+CD1a+CD11b+ p-moDCs (Fig 5, G; ± 1 μg of Pam3CSK4; n = 3). Journal of Allergy and Clinical Immunology 2017 139, 1873-1884.e10DOI: (10.1016/j.jaci.2016.09.018) Copyright © 2016 The Authors Terms and Conditions

Fig 6 RUNX3 and KLF4 are inversely regulated during LC and moDC differentiation. A and B, KLF4 and RUNX3 protein expression of day 5 p-LC precursors (Fig 6, A) and CD14+ monocytes (Fig 6, B). C, FACS of GFP+ day 5 precursors (n = 5). *P < .05, t test. D and E, FACS of GFP+ day 5 precursors subcultured under p-LC–promoting (+/-TGF-β1; Fig 6, D) or p-moDC–promoting (Fig 6, E; GM-CSF plus IL-4) conditions at day 7 (n = 6). *P < .05, t test; ***P < .001. Journal of Allergy and Clinical Immunology 2017 139, 1873-1884.e10DOI: (10.1016/j.jaci.2016.09.018) Copyright © 2016 The Authors Terms and Conditions

Fig 7 RUNX3 restores LC differentiation from KLF4-transduced progenitors. A-C, RUNX3 protein (Fig 7, A) and RUNX3, TIEG, and SMAD7 mRNA (Fig 7, B and C) expression of GFP+ day 5 precursors cultivated with or without TGF-β1. D, Semiquantitative PCR analysis of KLF4 chromatin immunoprecipitation from CD1a+ moDCs (n = 3). E and F, FACS analysis of cotransduced GFP+NGFR+-gated day 5 precursors (Fig 7, E) and p-LCs (Fig 7, F; +TGF-β1; n = 6). *P < .05, **P < .01, and ***P < .001, t test. Journal of Allergy and Clinical Immunology 2017 139, 1873-1884.e10DOI: (10.1016/j.jaci.2016.09.018) Copyright © 2016 The Authors Terms and Conditions

Fig E1 Immunohistochemical analysis of healthy human skin and in vitro–generated LCs. A, Paraffin sections of healthy human skin were stained for CD1a (red) and aN1 (blue). Bars = 10 μm. B, p-LCs and moLCs were sorted by using anti-CD207 mAb with magnetic beads. Cells were spun on slides, fixed, permeabilized and stained for CD1a and aN1. Bars = 10 μm. Journal of Allergy and Clinical Immunology 2017 139, 1873-1884.e10DOI: (10.1016/j.jaci.2016.09.018) Copyright © 2016 The Authors Terms and Conditions

Fig E2 Analysis of the inhibitory role of KLF4 on LC-like cell differentiation. A and B, KLF4-IRES-GFP–, RUNX3-IRES-GFP–, or control-transduced day 5 precursors were cultured under LC-promoting conditions (+TGF-β1). GFP+CD1a+-gated cells were analyzed for expression of CD207, DC-specific intercellular adhesion molecule–grabbing nonintegrin (DC-SIGN; CD209), CD11b, and CD14. C, KLF4-IRES-GFP– or control-transduced cells were cultured under LC-promoting cytokine conditions (+TGF-β1). After 24 hours, GFP+ cells were sorted, and quantitative PCR analysis for ID2 mRNA expression was performed. Bar diagrams represent mean ± SEM values of 3 independent experiments. Journal of Allergy and Clinical Immunology 2017 139, 1873-1884.e10DOI: (10.1016/j.jaci.2016.09.018) Copyright © 2016 The Authors Terms and Conditions