The PD-1/PD-L pathway is up-regulated during IL-12-induced suppression of EAE mediated by IFN-gamma.
Experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), is mediated by autoantigen-specific T-helper1 (Th1) cells. IL-12, an inducer of Th1 cell development, exerts immunomodulatory effects in EAE. Programmed death-1 (PD-1) and PD-1 ligand (PD-L), new members of the B7 superfamily of costimulatory molecules, play a critical role in regulating EAE. Whether the interaction of IL-12 and the PD-1/PD-L pathway regulates EAE is unclear. We have previously shown that IL-12 suppresses EAE induced by MOG35-55 in C57BL/6 mice, but not in IFN-gamma-deficient mice, suggesting that IFN-gamma is required for the inhibitory effects of IL-12 on EAE. In the current study, PD-L1 expression is up-regulated following IL-12 treatment in wild-type mice, but not in IFN-(-deficient EAE mice. Similarly, IL-12 induces IFN-gamma and PD-L1 expression in cultured MOG-specific T cells from wild-type mice but not from IFN-gamma-deficient mice. Furthermore, PD-L1 expression increased specifically in CD11b+ antigen presenting cells (APCs) after IL-12 administration. These data suggest that one mechanism of IL-12 suppression of EAE is mediated by PD-1/PD-L signaling downstream of IFN-gamma induction in CD11b+ APCs. The regulation of PD-1/PD-L1 may have potential therapeutic effects for EAE and MS.
Cheng
Xiaodong
X
Department of Neurology, Jefferson Hospital for Neuroscience, Thomas Jefferson University, 900 Walnut Street, Philadelphia, PA 19107, USA.
Zhao
Zhao
Z
Ventura
Elvira
E
Gran
Bruno
B
Shindler
Kenneth S
KS
Rostami
Abdolmohamad
A
D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D000943:Antigens, Differentiation / Q000276:immunology* / Q000378:metabolism; D018122:B7-1 Antigen / Q000276:immunology* / Q000378:metabolism; D060890:B7-H1 Antigen; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D015870:Gene Expression; D006023:Glycoproteins / Q000276:immunology; D007371:Interferon-gamma / Q000378:metabolism*; D018664:Interleukin-12 / Q000276:immunology* / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments / Q000276:immunology; D010455:Peptides / Q000276:immunology* / Q000378:metabolism; D061026:Programmed Cell Death 1 Receptor; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000276:immunology
D000943:Antigens, Differentiation; D018122:B7-1 Antigen; D060890:B7-H1 Antigen; C498919:Cd274 protein, mouse; D006023:Glycoproteins; D008562:Membrane Glycoproteins; D063308:Myelin-Oligodendrocyte Glycoprotein; C491383:Pdcd1 protein, mouse; D010446:Peptide Fragments; D010455:Peptides; D061026:Programmed Cell Death 1 Receptor; C445081:myelin oligodendrocyte glycoprotein (35-55); D018664:Interleukin-12; D007371:Interferon-gamma