Critical role of the programmed death-1 (PD-1) pathway in regulation of experimental autoimmune encephalomyelitis.
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.
Salama
Alan D
AD
Laboratory of Immunogenetics and Transplantation, Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Chitnis
Tanuja
T
Imitola
Jaime
J
Ansari
Mohammed Javeed I
MJ
Akiba
Hisaya
H
Tushima
Fumihiko
F
Azuma
Miyuki
M
Yagita
Hideo
H
Sayegh
Mohamed H
MH
Khoury
Samia J
SJ
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
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