title: Cutaneous innate immune sensing of Toll-like receptor 2-6 ligands suppresses T cell immunity by inducing myeloid-derived suppressor cells.
abstract: Skin is constantly exposed to bacteria and antigens, and cutaneous innate immune sensing orchestrates adaptive immune responses. In its absence, skin pathogens can expand, entering deeper tissues and leading to life-threatening infectious diseases. To characterize skin-driven immunity better, we applied living bacteria, defined lipopeptides, and antigens cutaneously. We found suppression of immune responses due to cutaneous infection with Gram-positive S. aureus, which was based on bacterial lipopeptides. Skin exposure to Toll-like receptor (TLR)2-6-binding lipopeptides, but not TLR2-1-binding lipopeptides, potently suppressed immune responses through induction of Gr1(+)CD11b(+) myeloid-derived suppressor cells (MDSCs). Investigating human atopic dermatitis, in which Gram-positive bacteria accumulate, we detected high MDSC amounts in blood and skin. TLR2 activation in skin resident cells triggered interleukin-6 (IL-6), which induced suppressive MDSCs, which are then recruited to the skin suppressing T cell-mediated recall responses such as dermatitis. Thus, cutaneous bacteria can negatively regulate skin-driven immune responses by inducing MDSCs via TLR2-6 activation.
authors.affiliation: Department of Dermatology, Eberhard Karls University, Liebermeisterstrasse 25, 72076 Tübingen, Germany.
authors.forename: Yuliya
authors.initials: Y
authors.lastname: Skabytska
authors.affiliation: Department of Dermatology, Eberhard Karls University, Liebermeisterstrasse 25, 72076 Tübingen, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Wölbing
authors.affiliation: Department of Dermatology, Technical University Dresden, Mommsenstrasse 11, 01069 Dresden, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Günther
authors.affiliation: Department of Dermatology, Eberhard Karls University, Liebermeisterstrasse 25, 72076 Tübingen, Germany; Department of Dermatology and Allergy, Technische Universität München, Biedersteinerstrasse 29, 80802 Munich, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Köberle
authors.affiliation: Department of Dermatology, Eberhard Karls University, Liebermeisterstrasse 25, 72076 Tübingen, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Kaesler
authors.affiliation: Department of Dermatology, Eberhard Karls University, Liebermeisterstrasse 25, 72076 Tübingen, Germany.
authors.forename: Ko-Ming
authors.initials: KM
authors.lastname: Chen
authors.affiliation: Department of Dermatology, Eberhard Karls University, Liebermeisterstrasse 25, 72076 Tübingen, Germany; Department of Dermatology, University Hospital Zurich, Gloriastrasse 31, CH-8091 Zurich, Switzerland.
authors.forename: Emmanuella
authors.initials: E
authors.lastname: Guenova
authors.affiliation: Department of Microbial Genetics, Eberhard Karls University, Waldhäuser Straße 70/8, 72076 Tübingen, Germany.
authors.forename: Doruk
authors.initials: D
authors.lastname: Demircioglu
authors.affiliation: Department of Dermatology, Eberhard Karls University, Liebermeisterstrasse 25, 72076 Tübingen, Germany; Department of Dermatology and Allergy, Technische Universität München, Biedersteinerstrasse 29, 80802 Munich, Germany.
authors.forename: Wolfgang E
authors.initials: WE
authors.lastname: Kempf
authors.affiliation: Department of Dermatology, Eberhard Karls University, Liebermeisterstrasse 25, 72076 Tübingen, Germany; Department of Dermatology and Allergy, Technische Universität München, Biedersteinerstrasse 29, 80802 Munich, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Volz
authors.affiliation: Department of Immunology, Institute of Cell Biology, and German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ) Partner Site Tübingen, Eberhard Karls University, Auf der Morgenstelle 15, 72076 Tübingen, Germany.
authors.forename: Hans-Georg
authors.initials: HG
authors.lastname: Rammensee
authors.affiliation: Department of Dermatology, Eberhard Karls University, Liebermeisterstrasse 25, 72076 Tübingen, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Schaller
authors.affiliation: Department of Dermatology, Eberhard Karls University, Liebermeisterstrasse 25, 72076 Tübingen, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Röcken
authors.affiliation: Department of Microbial Genetics, Eberhard Karls University, Waldhäuser Straße 70/8, 72076 Tübingen, Germany.
authors.forename: Friedrich
authors.initials: F
authors.lastname: Götz
authors.affiliation: Department of Dermatology, Eberhard Karls University, Liebermeisterstrasse 25, 72076 Tübingen, Germany; Department of Dermatology and Allergy, Technische Universität München, Biedersteinerstrasse 29, 80802 Munich, Germany. Electronic address: tilo.biedermann@tum.de.
authors.forename: Tilo
authors.initials: T
authors.lastname: Biedermann
mesh_terms: D056704:Adaptive Immunity / Q000276:immunology; D000818:Animals; D000941:Antigens / Q000276:immunology; D039481:CD11b Antigen / Q000096:biosynthesis; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D003876:Dermatitis, Atopic / Q000276:immunology / Q000382:microbiology; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis; D055666:Lipopeptides / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000276:immunology*; D053594:Myeloid Differentiation Factor 88 / Q000096:biosynthesis; D012867:Skin / Q000276:immunology* / Q000382:microbiology; D013207:Staphylococcal Skin Infections / Q000276:immunology*; D013211:Staphylococcus aureus / Q000276:immunology; D051194:Toll-Like Receptor 1 / Q000276:immunology; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000276:immunology; D051216:Toll-Like Receptor 6 / Q000276:immunology
chemical_list: D000941:Antigens; D039481:CD11b Antigen; D015850:Interleukin-6; D055666:Lipopeptides; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; C495369:Tlr6 protein, mouse; D051194:Toll-Like Receptor 1; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051216:Toll-Like Receptor 6