title: B7-H1 restricts neuroantigen-specific T cell responses and confines inflammatory CNS damage: implications for the lesion pathogenesis of multiple sclerosis.
abstract: The co-inhibitory B7-homologue 1 (B7-H1/PD-L1) influences adaptive immune responses and has been proposed to contribute to the mechanisms maintaining peripheral tolerance and limiting inflammatory damage in parenchymal organs. To understand the B7-H1/PD1 pathway in CNS inflammation, we analyzed adaptive immune responses in myelin oligodendrocyte glycoprotein (MOG)(35-55)-induced EAE and assessed the expression of B7-H1 in human CNS tissue. B7-H1(-/-) mice exhibited an accelerated disease onset and significantly exacerbated EAE severity, although absence of B7-H1 had no influence on MOG antibody production. Peripheral MOG-specific IFN-gamma/IL-17 T cell responses occurred earlier and enhanced in B7-H1(-/-) mice, but ceased more rapidly. In the CNS, however, significantly higher numbers of activated neuroantigen-specific T cells persisted during all stages of EAE. Experiments showing a direct inhibitory role of APC-derived B7-H1 on the activation of MOG-specific effector cells support the assumption that parenchymal B7-H1 is pivotal for delineating T cell fate in the target organ. Compatible with this concept, our data investigating human brain tissue specimens show a strong up-regulation of B7-H1 in lesions of multiple sclerosis. Our findings demonstrate the critical importance of B7-H1 as an immune-inhibitory molecule capable of down-regulating T cell responses thus contributing to the confinement of immunopathological damage.
authors.affiliation: Clinical Research Group for Multiple Sclerosis and Neuroimmunology, Department of Neurology, University of Würzburg, Würzburg, Germany.
authors.forename: Sonja
authors.initials: S
authors.lastname: Ortler
authors.forename: Christoph
authors.initials: C
authors.lastname: Leder
authors.forename: Michel
authors.initials: M
authors.lastname: Mittelbronn
authors.forename: Alla L
authors.initials: AL
authors.lastname: Zozulya
authors.forename: Percy A
authors.initials: PA
authors.lastname: Knolle
authors.forename: Lieping
authors.initials: L
authors.lastname: Chen
authors.forename: Antje
authors.initials: A
authors.lastname: Kroner
authors.forename: Heinz
authors.initials: H
authors.lastname: Wiendl
mesh_terms: D000818:Animals; D000917:Antibody Formation / Q000276:immunology; D000938:Antigen-Presenting Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D015703:Antigens, CD / Q000032:analysis; D017209:Apoptosis / Q000276:immunology; D018122:B7-1 Antigen / Q000276:immunology*; D060890:B7-H1 Antigen; D002452:Cell Count; D002490:Central Nervous System / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D006023:Glycoproteins / Q000276:immunology; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism; D007700:Kinetics; D008213:Lymphocyte Activation / Q000276:immunology; D008562:Membrane Glycoproteins / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009103:Multiple Sclerosis / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein / Q000276:immunology*; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments / Q000276:immunology; D010455:Peptides / Q000276:immunology*; D013154:Spleen / Q000166:cytology / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D014611:Vaccination
chemical_list: D015703:Antigens, CD; D018122:B7-1 Antigen; D060890:B7-H1 Antigen; C498919:Cd274 protein, mouse; D006023:Glycoproteins; D020381:Interleukin-17; C571326:MOG protein, human; D008562:Membrane Glycoproteins; C571327:Mog protein, mouse; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; D010455:Peptides; C445081:myelin oligodendrocyte glycoprotein (35-55); D007371:Interferon-gamma