title: B7-H1 Selectively Controls TH17 Differentiation and Central Nervous System Autoimmunity via a Novel Non-PD-1-Mediated Pathway.
abstract: It is currently acknowledged that TH17 cells are critically involved in the pathogenesis of autoimmune diseases such as multiple sclerosis (MS). In this article, we demonstrate that signals delivered by the coinhibitory molecule B7-homologue 1 (B7-H1) via a B7-homologue 1 mouse-IgG2aFc (B7-H1-Ig) fusion protein nearly abolish TH17, but not TH1 and TH2, differentiation via direct interaction with the T cell. These effects were equally pronounced in the absence of programmed death-1 or B7.1 and B7.2 on the T cell side, thus providing clear evidence that B7-H1 modulates T cell differentiation via a novel receptor. Mechanistically, B7-H1 interfered with early TCR-mediated signaling and cytokine-mediated induction of the TH17-determining transcription factors retinoic acid-related orphan receptor γ t and IFN regulator factor-4 in a programmed death-1 and B7-independent fashion. In an animal model of MS, active myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis, B7-H1-Ig exhibited a significant and long-lasting effect on disease severity upon administration during the first 5 d of the priming phase, which was accompanied by reduced TH17 responses in the periphery and within the CNS. Importantly, B7-H1-Ig was even capable of interfering with T cell encephalitogenicity when interaction with the T cells occurred after priming using an adoptive transfer experimental autoimmune encephalomyelitis model. In line with this, both naive human CD4(+) T cells and differentiated TH17 effector cells from MS patients were highly sensitive toward B7-H1-Ig-mediated TH17 suppression. Together, we propose the existence of a novel B7-H1-mediated immune-regulatory pathway in T cells, which selectively limits murine and human TH17 cell responses and might be therapeutically exploited to control TH17-mediated autoimmunity.
authors.affiliation: Department of Neurology, University of Muenster, 48149 Muenster, Germany;
authors.forename: Martin
authors.initials: M
authors.lastname: Herold
authors.affiliation: Department of Neurology, University of Muenster, 48149 Muenster, Germany;
authors.forename: Vilmos
authors.initials: V
authors.lastname: Posevitz
authors.affiliation: Department of Neurology, University of Muenster, 48149 Muenster, Germany;
authors.forename: Daria
authors.initials: D
authors.lastname: Chudyka
authors.affiliation: Department of Neurology, University of Muenster, 48149 Muenster, Germany;
authors.forename: Stephanie
authors.initials: S
authors.lastname: Hucke
authors.affiliation: Department of Neurology, University of Muenster, 48149 Muenster, Germany;
authors.forename: Catharina
authors.initials: C
authors.lastname: Groß
authors.affiliation: Department of Neurology, University of Muenster, 48149 Muenster, Germany;
authors.forename: Frank
authors.initials: F
authors.lastname: Kurth
authors.affiliation: Experimental Cardiology, University of Tuebingen, 72076 Tuebingen, Germany;
authors.forename: Christoph
authors.initials: C
authors.lastname: Leder
authors.affiliation: Department of Dermatology, University of Muenster, 48149 Muenster, Germany;
authors.forename: Karin
authors.initials: K
authors.lastname: Loser
authors.affiliation: Institute of Experimental Immunology, University Clinic Bonn, 53127 Bonn, Germany; and.
authors.forename: Christian
authors.initials: C
authors.lastname: Kurts
authors.affiliation: Institute of Molecular Immunology, Technical University Munich, 81675 Munich, Germany.
authors.forename: Percy
authors.initials: P
authors.lastname: Knolle
authors.affiliation: Department of Neurology, University of Muenster, 48149 Muenster, Germany; heinz.wiendl@ukmuenster.de luisa.klotz@ukmuenster.de.
authors.forename: Luisa
authors.initials: L
authors.lastname: Klotz
authors.affiliation: Department of Neurology, University of Muenster, 48149 Muenster, Germany; heinz.wiendl@ukmuenster.de luisa.klotz@ukmuenster.de.
authors.forename: Heinz
authors.initials: H
authors.lastname: Wiendl
mesh_terms: D000818:Animals; D060890:B7-H1 Antigen / Q000235:genetics / Q000276:immunology*; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009103:Multiple Sclerosis / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D061026:Programmed Cell Death 1 Receptor / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D058504:Th17 Cells / Q000276:immunology* / Q000473:pathology
chemical_list: D060890:B7-H1 Antigen; C423236:CD274 protein, human; C498919:Cd274 protein, mouse; C105992:PDCD1 protein, human; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor