title: IL-1β-dependent activation of dendritic epidermal T cells in contact hypersensitivity.
abstract: Substances that penetrate the skin surface can act as allergens and induce a T cell-mediated inflammatory skin disease called contact hypersensitivity (CHS). IL-17 is a key cytokine in CHS and was originally thought to be produced solely by CD4(+) T cells. However, it is now known that several cell types, including γδ T cells, can produce IL-17. In this study, we determine the role of γδ T cells, especially dendritic epidermal T cells (DETCs), in CHS. Using a well-established model for CHS in which 2,4-dinitrofluorobenzene (DNFB) is used as allergen, we found that γδ T cells are important players in CHS. Thus, more IL-17-producing DETCs appear in the skin following exposure to DNFB in wild-type mice, and DNFB-induced ear swelling is reduced by ∼50% in TCRδ(-/-) mice compared with wild-type mice. In accordance, DNFB-induced ear swelling was reduced by ∼50% in IL-17(-/-) mice. We show that DNFB triggers DETC activation and IL-1β production in the skin and that keratinocytes produce IL-1β when stimulated with DNFB. We find that DETCs activated in vitro by incubation with anti-CD3 and IL-1β produce IL-17. Importantly, we demonstrate that the IL-1R antagonist anakinra significantly reduces CHS responses, as measured by decreased ear swelling, inhibition of local DETC activation, and a reduction in the number of IL-17(+) γδ T cells and DETCs in the draining lymph nodes. Taken together, we show that DETCs become activated and produce IL-17 in an IL-1β-dependent manner during CHS, suggesting a key role for DETCs in CHS.
authors.affiliation: Department of International Health, Immunology, and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark;
authors.forename: Morten M
authors.initials: MM
authors.lastname: Nielsen
authors.forename: Paola
authors.initials: P
authors.lastname: Lovato
authors.forename: Amanda S
authors.initials: AS
authors.lastname: MacLeod
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Witherden
authors.forename: Lone
authors.initials: L
authors.lastname: Skov
authors.forename: Beatrice
authors.initials: B
authors.lastname: Dyring-Andersen
authors.forename: Sally
authors.initials: S
authors.lastname: Dabelsteen
authors.forename: Anders
authors.initials: A
authors.lastname: Woetmann
authors.forename: Niels
authors.initials: N
authors.lastname: Ødum
authors.forename: Wendy L
authors.initials: WL
authors.lastname: Havran
authors.forename: Carsten
authors.initials: C
authors.lastname: Geisler
authors.forename: Charlotte M
authors.initials: CM
authors.lastname: Bonefeld
mesh_terms: D000818:Animals; D002460:Cell Line; D003877:Dermatitis, Contact / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D004139:Dinitrofluorobenzene / Q000276:immunology; D005434:Flow Cytometry; D015870:Gene Expression / Q000276:immunology; D020381:Interleukin-17 / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D053583:Interleukin-1beta / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D015603:Keratinocytes / Q000276:immunology / Q000378:metabolism; D007801:Langerhans Cells / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology*; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012867:Skin / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism
chemical_list: D020381:Interleukin-17; D053583:Interleukin-1beta; D016692:Receptors, Antigen, T-Cell, gamma-delta; D004139:Dinitrofluorobenzene