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 -