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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.
AuthorsSonja Ortler, Christoph Leder, Michel Mittelbronn, Alla L Zozulya, Percy A Knolle, Lieping Chen, Antje Kroner, Heinz Wiendl
JournalEuropean journal of immunology (Eur J Immunol) Vol. 38 Issue 6 Pg. 1734-44 (Jun 2008) ISSN: 0014-2980 [Print] Germany
PMID18421793 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Antigens, CD
  • B7-1 Antigen
  • B7-H1 Antigen
  • Cd274 protein, mouse
  • Glycoproteins
  • Interleukin-17
  • MOG protein, human
  • Membrane Glycoproteins
  • Mog protein, mouse
  • Myelin Proteins
  • Myelin-Associated Glycoprotein
  • Myelin-Oligodendrocyte Glycoprotein
  • Peptide Fragments
  • Peptides
  • myelin oligodendrocyte glycoprotein (35-55)
  • Interferon-gamma
Topics
  • Animals
  • Antibody Formation (immunology)
  • Antigen-Presenting Cells (cytology, immunology, metabolism)
  • Antigens, CD (analysis)
  • Apoptosis (immunology)
  • B7-1 Antigen (immunology)
  • B7-H1 Antigen
  • Cell Count
  • Central Nervous System (immunology, metabolism, pathology)
  • Disease Models, Animal
  • Glycoproteins (immunology)
  • Humans
  • Interferon-gamma (metabolism)
  • Interleukin-17 (metabolism)
  • Kinetics
  • Lymphocyte Activation (immunology)
  • Membrane Glycoproteins (immunology)
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Multiple Sclerosis (immunology, metabolism, pathology)
  • Myelin Proteins
  • Myelin-Associated Glycoprotein (immunology)
  • Myelin-Oligodendrocyte Glycoprotein
  • Peptide Fragments (immunology)
  • Peptides (immunology)
  • Spleen (cytology, immunology)
  • T-Lymphocyte Subsets (cytology, immunology, metabolism)
  • T-Lymphocytes (cytology, immunology, metabolism)
  • Vaccination

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