J Exp Med. 2003 Jul 7;198(1):71-8
Salama AD, Chitnis T, Imitola J, Akiba H, Tushima F, Azuma M, Yagita H, Sayegh MH, Khoury SJ.
77 Avenue Louis Pasteur, Room 714, Centre for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA 02115.
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.