B7-H1 restricts neuroantigen-specific T cell responses and confines inflammatory CNS damage: implications for the lesion pathogenesis of multiple sclerosis.
Publikation: Beiträge in Zeitschriften › Zeitschriftenaufsätze › Forschung
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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. / Ortler, Sonja; Leder, Christoph; Mittelbronn, Michel et al.
in: European Journal of Immunology, Jahrgang 38, Nr. 6, 06.2008, S. 1734-1744.Publikation: Beiträge in Zeitschriften › Zeitschriftenaufsätze › Forschung
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TY - JOUR
T1 - B7-H1 restricts neuroantigen-specific T cell responses and confines inflammatory CNS damage: implications for the lesion pathogenesis of multiple sclerosis.
AU - Ortler, Sonja
AU - Leder, Christoph
AU - Mittelbronn, Michel
AU - Zozulya, Alla L.
AU - Knolle, Percy A.
AU - Kroner, Antje
AU - Wiendl, Heinz
AU - Chen, Lieping
PY - 2008/6
Y1 - 2008/6
N2 - 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-γ/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.
AB - 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-γ/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.
KW - Chemistry
KW - Co-stimulation
KW - EAE
KW - Inflammation
KW - MS
UR - http://www.scopus.com/inward/record.url?scp=49649111913&partnerID=8YFLogxK
UR - https://www.mendeley.com/catalogue/e246980c-d867-3c04-96f8-094c430d852a/
U2 - 10.1002/eji.200738071
DO - 10.1002/eji.200738071
M3 - Journal articles
VL - 38
SP - 1734
EP - 1744
JO - European Journal of Immunology
JF - European Journal of Immunology
SN - 0014-2980
IS - 6
ER -