title: The glucocorticoid-induced TNF receptor-related protein (GITR)-GITR ligand pathway acts as a mediator of cutaneous dendritic cell migration and promotes T cell-mediated acquired immunity.
abstract: Glucocorticoid-induced TNFR-related protein (GITR) has various roles in the activation of T cells and inflammation. In this study, we investigated the roles of the GITR-GITR ligand (GITRL) pathway in contact hypersensitivity (CH). Treatment with anti-GITRL mAb at sensitization inhibited CH responses. Depletion studies using an anti-CD25 or anti-PDCA-1 mAb revealed that regulatory T cells and plasmacytoid dendritic cells (DCs), known to express high levels of GITR and GITRL, respectively, were not apparently involved in GITRL-mediated CH responses. Treatment with/addition of anti-GITRL mAb in the experiments for hapten-specific T cell proliferation and IFN-gamma production showed a minor contribution of the GITRL, which was weakly expressed on DCs in draining lymph nodes (dLNs). Interestingly, anti-GITRL mAb treatment inhibited the migration of cutaneous DCs to the dLNs. Epidermal keratinocytes (KCs) constitutively express GITR, whereas Langerhans cells (LCs) express higher levels of GITRL compared with DCs in dLNs. GITR ligation, by an anti-GITR mAb, in KCs promoted expression of multiple proinflammatory cytokines and blockade of GITRL-inhibited IL-1beta and CCR7 expression in sensitized skin. These results suggest that the GITR-GITRL pathway promotes epidermal inflammatory cytokine production by KCs and LCs, resulting in migration of cutaneous DCs from the skin to the dLNs. This is the first report demonstrating the involvement of the GITR-GTRL pathway in interactions with KCs and LCs and the migration of DCs. Our findings provide important implications for understanding the molecular bases of KC-LC interactions and for developing new therapeutic strategies in skin disease.
authors.affiliation: Department of Molecular Immunology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Kamimura
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Iwai
authors.forename: Jinhua
authors.initials: J
authors.lastname: Piao
authors.forename: Masaaki
authors.initials: M
authors.lastname: Hashiguchi
authors.forename: Miyuki
authors.initials: M
authors.lastname: Azuma
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D002450:Cell Communication / Q000276:immunology*; D002464:Cell Migration Inhibition / Q000276:immunology; D002465:Cell Movement / Q000276:immunology*; D002478:Cells, Cultured; D018920:Coculture Techniques; D003877:Dermatitis, Contact / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D004139:Dinitrofluorobenzene / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000276:immunology; D005260:Female; D053450:Glucocorticoid-Induced TNFR-Related Protein; D006241:Haptens / Q000008:administration & dosage / Q000276:immunology; D015603:Keratinocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D007801:Langerhans Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008024:Ligands; D008198:Lymph Nodes / Q000276:immunology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D017475:Receptors, Nerve Growth Factor / Q000037:antagonists & inhibitors / Q000276:immunology / Q000502:physiology*; D018124:Receptors, Tumor Necrosis Factor / Q000037:antagonists & inhibitors / Q000276:immunology / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D048069:Tumor Necrosis Factors / Q000502:physiology*
chemical_list: D000911:Antibodies, Monoclonal; D053450:Glucocorticoid-Induced TNFR-Related Protein; D006241:Haptens; D008024:Ligands; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; C106544:Tnfrsf18 protein, mouse; C478966:Tnfsf18 protein, mouse; D048069:Tumor Necrosis Factors; D004139:Dinitrofluorobenzene; C002041:1,5-difluoro-2,4-dinitrobenzene