title: Pathogenic Function of Herpesvirus Entry Mediator in Experimental Autoimmune Uveitis by Induction of Th1- and Th17-Type T Cell Responses.
abstract: Herpesvirus entry mediator (HVEM), a member of the TNFR superfamily, serves as a unique molecular switch to mediate both stimulatory and inhibitory cosignals, depending on its functions as a receptor or ligand interacting with multiple binding partners. In this study, we explored the cosignaling functions of HVEM in experimental autoimmune uveitis (EAU), a mouse model resembling human autoimmune uveitis conditions such as ocular sarcoidosis and Behcet disease. Our studies revealed that EAU severity significantly decreased in HVEM-knockout mice compared with wild-type mice, suggesting that stimulatory cosignals from the HVEM receptor are predominant in EAU. Further studies elucidated that the HVEM cosignal plays an important role in the induction of both Th1- and Th17-type pathogenic T cells in EAU, including differentiation of IL-17-producing αβ(+)γδ(-) conventional CD4(+) T cells. Mice lacking lymphotoxin-like, inducible expression, competes with herpes simplex virus glycoprotein D for HVEM, a receptor expressed by T lymphocytes : LIGHT), B- and T-lymphocyte attenuator (BTLA) or both LIGHT and BTLA are also less susceptible to EAU, indicating that LIGHT-HVEM and BTLA-HVEM interactions, two major molecular pathways mediating HVEM functions, are both important in determining EAU pathogenesis. Finally, blocking HVEM cosignals by antagonistic anti-HVEM Abs ameliorated EAU. Taken together, our studies revealed a novel function of the HVEM cosignaling molecule and its ligands in EAU pathogenesis through the induction of Th1- and Th17-type T cell responses and suggested that HVEM-related molecular pathways can be therapeutic targets in autoimmune uveitis.
authors.affiliation: Department of Immunology, Yamaguchi University Graduate School of Medicine, Ube City, Yamaguchi 755-8505, Japan; and.
authors.forename: Yukimi
authors.identifier: http://orcid.org/0000-0003-1519-893X
authors.initials: Y
authors.lastname: Sakoda
authors.affiliation: Department of Immunology, Yamaguchi University Graduate School of Medicine, Ube City, Yamaguchi 755-8505, Japan; and Department of Ophthalmology, Yamaguchi University Graduate School of Medicine, Ube City, Yamaguchi 755-8505, Japan.
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Nagai
authors.affiliation: Department of Ophthalmology, Yamaguchi University Graduate School of Medicine, Ube City, Yamaguchi 755-8505, Japan.
authors.forename: Sizuka
authors.initials: S
authors.lastname: Murata
authors.affiliation: Department of Ophthalmology, Yamaguchi University Graduate School of Medicine, Ube City, Yamaguchi 755-8505, Japan.
authors.forename: Yukari
authors.initials: Y
authors.lastname: Mizuno
authors.affiliation: Department of Immunology, Yamaguchi University Graduate School of Medicine, Ube City, Yamaguchi 755-8505, Japan; and.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Kurosawa
authors.affiliation: Department of Ophthalmology, Yamaguchi University Graduate School of Medicine, Ube City, Yamaguchi 755-8505, Japan.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Shoda
authors.affiliation: Department of Ophthalmology, Yamaguchi University Graduate School of Medicine, Ube City, Yamaguchi 755-8505, Japan.
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Morishige
authors.affiliation: Department of Ophthalmology, Yamaguchi University Graduate School of Medicine, Ube City, Yamaguchi 755-8505, Japan.
authors.forename: Ryoji
authors.initials: R
authors.lastname: Yanai
authors.affiliation: Department of Ophthalmology, Yamaguchi University Graduate School of Medicine, Ube City, Yamaguchi 755-8505, Japan.
authors.forename: Koh-Hei
authors.initials: KH
authors.lastname: Sonoda
authors.affiliation: Department of Immunology, Yamaguchi University Graduate School of Medicine, Ube City, Yamaguchi 755-8505, Japan; and ktamada@yamaguchi-u.ac.jp.
authors.forename: Koji
authors.initials: K
authors.lastname: Tamada
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001327:Autoimmune Diseases / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D008024:Ligands; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D011971:Receptors, Immunologic / Q000378:metabolism; D053240:Receptors, Tumor Necrosis Factor, Member 14 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D058504:Th17 Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14 / Q000378:metabolism; D014605:Uveitis / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; C488868:BTLA protein, mouse; D016207:Cytokines; D008024:Ligands; D011971:Receptors, Immunologic; D053240:Receptors, Tumor Necrosis Factor, Member 14; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14