title: Cutaneous RANK-RANKL Signaling Upregulates CD8-Mediated Antiviral Immunity during Herpes simplex Virus Infection by Preventing Virus-Induced Langerhans Cell Apoptosis.
abstract: Herpes simplex virus-type 1 (HSV-1) causes the majority of cutaneous viral infections. Viral infections are controlled by the immune system, and CD8(+) cytotoxic T-lymphocytes (CTLs) have been shown to be crucial during the clearance of HSV-1 infections. Although epidermal Langerhans cells (LCs) are the first dendritic cells (DCs) to come into contact with the virus, it has been shown that the processing of viral antigens and the differentiation of antiviral CTLs are mediated by migratory CD103(+) dermal DCs and CD8α(+) lymph node-resident DCs. In vivo regulatory T-cells (Tregs) are implicated in the regulation of antiviral immunity and we have shown that signaling via the receptor activator of NF-κB (RANK) and its ligand RANKL mediates the peripheral expansion of Tregs. However, in addition to expanding Tregs, RANK-RANKL interactions are involved in the control of antimicrobial immunity by upregulating the priming of CD4(+) effector T cells in LCMV infection or by the generation of parasite-specific CD8(+) T cells in Trypanosoma cruzi infection. Here, we demonstrate that cutaneous RANK-RANKL signaling is critical for the induction of CD8-mediated antiviral immune responses during HSV-1 infection of the skin by preventing virus-induced LC apoptosis, improving antigen transport to regional lymph nodes, and increasing the CTL priming capacity of lymph node DCs.
authors.affiliation: Department of Dermatology, University of Münster, Münster, Germany; Collaborative Research Centre 1009, University of Münster, Münster, Germany.
authors.forename: Lars
authors.initials: L
authors.lastname: Klenner
authors.affiliation: Department of Medical Microbiology, University of Münster, Münster, Germany.
authors.forename: Wali
authors.initials: W
authors.lastname: Hafezi
authors.affiliation: Institute for Molecular Medicine, University of Mainz, Mainz, Germany.
authors.forename: Björn E
authors.initials: BE
authors.lastname: Clausen
authors.affiliation: Collaborative Research Centre 656, University of Münster, Münster, Germany.
authors.forename: Eva U
authors.initials: EU
authors.lastname: Lorentzen
authors.affiliation: Department of Dermatology, University of Münster, Münster, Germany.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Luger
authors.affiliation: Department of Dermatology, University of Münster, Münster, Germany; Department of Dermatology, Technical University of Dresden, Dresden, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Beissert
authors.affiliation: Department of Medical Microbiology, University of Münster, Münster, Germany.
authors.forename: Joachim E
authors.initials: JE
authors.lastname: Kühn
authors.affiliation: Department of Dermatology, University of Münster, Münster, Germany; Collaborative Research Centre 1009, University of Münster, Münster, Germany; Interdisciplinary Center for Clinical Research-IZKF, University of Münster, Münster, Germany; Cells in Motion - Cluster of Excellence, University of Münster, Münster, Germany. Electronic address: loserk@uni-muenster.de.
authors.forename: Karin
authors.initials: K
authors.lastname: Loser
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000276:immunology; D015415:Biomarkers / Q000378:metabolism; D016827:CD8 Antigens / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D006561:Herpes Simplex / Q000276:immunology* / Q000378:metabolism; D018259:Herpesvirus 1, Human / Q000276:immunology; D006801:Humans; D007109:Immunity / Q000502:physiology; D007801:Langerhans Cells / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D053245:RANK Ligand / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D011897:Random Allocation; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000235:genetics / Q000276:immunology*; D012680:Sensitivity and Specificity; D015398:Signal Transduction; D015854:Up-Regulation
chemical_list: D015415:Biomarkers; D016827:CD8 Antigens; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; C505687:Tnfrsf11a protein, mouse; C505689:Tnfsf11 protein, mouse