title: Critical role of the programmed death-1 (PD-1) pathway in regulation of experimental autoimmune encephalomyelitis.
abstract: Experimental autoimmune encephalomyelitis (EAE) is mediated by autoantigen-specific T cells dependent on critical costimulatory signals for their full activation and regulation. We report that the programmed death-1 (PD-1) costimulatory pathway plays a critical role in regulating peripheral tolerance in murine EAE and appears to be a major contributor to the resistance of disease induction in CD28-deficient mice. After immunization with myelin oligodendrocyte glycoprotein (MOG) there was a progressive increase in expression of PD-1 and its ligand PD-L1 but not PD-L2 within the central nervous system (CNS) of mice with EAE, peaking after 3 wk. In both wild-type (WT) and CD28-deficient mice, PD-1 blockade resulted in accelerated and more severe disease with increased CNS lymphocyte infiltration. Worsening of disease after PD-1 blockade was associated with a heightened autoimmune response to MOG, manifested by increased frequency of interferon gamma-producing T cells, increased delayed-type hypersensitivity responses, and higher serum levels of anti-MOG antibody. In vivo blockade of PD-1 resulted in increased antigen-specific T cell expansion, activation, and cytokine production. Interestingly, PD-L2 but not PD-L1 blockade in WT animals also resulted in disease augmentation. Our data are the first demonstration that the PD-1 pathway plays a critical role in regulating EAE.
authors.affiliation: Laboratory of Immunogenetics and Transplantation, Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Alan D
authors.initials: AD
authors.lastname: Salama
authors.forename: Tanuja
authors.initials: T
authors.lastname: Chitnis
authors.forename: Jaime
authors.initials: J
authors.lastname: Imitola
authors.forename: Mohammed Javeed I
authors.initials: MJ
authors.lastname: Ansari
authors.forename: Hisaya
authors.initials: H
authors.lastname: Akiba
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Tushima
authors.forename: Miyuki
authors.initials: M
authors.lastname: Azuma
authors.forename: Hideo
authors.initials: H
authors.lastname: Yagita
authors.forename: Mohamed H
authors.initials: MH
authors.lastname: Sayegh
authors.forename: Samia J
authors.initials: SJ
authors.lastname: Khoury
mesh_terms: D000818:Animals; D000954:Antigens, Surface / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins; D018122:B7-1 Antigen; D060890:B7-H1 Antigen; D001798:Blood Proteins / Q000502:physiology; D018106:CD28 Antigens / Q000502:physiology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000209:etiology*; D005260:Female; D007371:Interferon-gamma / Q000096:biosynthesis; D008562:Membrane Glycoproteins; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein / Q000276:immunology; D063308:Myelin-Oligodendrocyte Glycoprotein; D010047:Ovalbumin / Q000276:immunology; D010455:Peptides / Q000502:physiology; D061027:Programmed Cell Death 1 Ligand 2 Protein; D061026:Programmed Cell Death 1 Receptor; D013116:Spinal Cord / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D000954:Antigens, Surface; D051017:Apoptosis Regulatory Proteins; D018122:B7-1 Antigen; D060890:B7-H1 Antigen; D001798:Blood Proteins; D018106:CD28 Antigens; C498919:Cd274 protein, mouse; D008562:Membrane Glycoproteins; C571327:Mog protein, mouse; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein; D063308:Myelin-Oligodendrocyte Glycoprotein; C491383:Pdcd1 protein, mouse; C556978:Pdcd1lg2 protein, mouse; D010455:Peptides; D061027:Programmed Cell Death 1 Ligand 2 Protein; D061026:Programmed Cell Death 1 Receptor; D007371:Interferon-gamma; D010047:Ovalbumin