B7-H1 restricts neuroantigen-specific T cell responses and confines inflammatory CNS damage: implications for the lesion pathogenesis of multiple sclerosis. Eur J Immunol 2008 Jun;38(6):1734-44
Date
04/19/2008Pubmed ID
18421793DOI
10.1002/eji.200738071Scopus ID
2-s2.0-49649111913 (requires institutional sign-in at Scopus site) 63 CitationsAbstract
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.
Author List
Ortler S, Leder C, Mittelbronn M, Zozulya AL, Knolle PA, Chen L, Kroner A, Wiendl HAuthor
Antje Kroner-Milsch MD, PhD Associate Professor in the Neurosurgery department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsAntibody Formation
Antigen-Presenting Cells
Antigens, CD
Apoptosis
B7-1 Antigen
B7-H1 Antigen
Cell Count
Central Nervous System
Disease Models, Animal
Glycoproteins
Humans
Interferon-gamma
Interleukin-17
Kinetics
Lymphocyte Activation
Membrane Glycoproteins
Mice
Mice, Inbred C57BL
Mice, Knockout
Multiple Sclerosis
Myelin Proteins
Myelin-Associated Glycoprotein
Myelin-Oligodendrocyte Glycoprotein
Peptide Fragments
Peptides
Spleen
T-Lymphocyte Subsets
T-Lymphocytes
Vaccination