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The Journal of Neuroscience, March 9, 2005, 25(10):2537-2546; doi:10.1523/JNEUROSCI.4794-04.2005

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Cellular/Molecular
Microglial Expression of the B7 Family Member B7 Homolog 1 Confers Strong Immune Inhibition: Implications for Immune Responses and Autoimmunity in the CNS

Tim Magnus,¹ Bettina Schreiner,² Thomas Korn,¹ Carolyn Jack,⁴ Hong Guo,² Jack Antel,⁴ Igal Ifergan,⁴ Lieping Chen,³ Felix Bischof,² Amit Bar-Or,⁴ and Heinz Wiendl^2,5

¹Department of Neurology, University of Homburg, D-66424 Homburg, Germany, ²Department of General Neurology, Hertie-Institute for Clinical Brain Research, University of Tuebingen, D-72076 Tuebingen, Germany, ³Department of Dermatology, Johns Hopkins University, Baltimore, Maryland 21205, ⁴Montreal Neurological Institute, McGill University Hospital, Montreal, Canada H3A 2T5, and ⁵Department of Neurology, University of Wuerzburg, D-97080, Wuerzburg, Germany

Inflammation of the CNS is usually locally limited to avoid devastating consequences. Critical players involved in this immune regulatory process are the resident immune cells of the brain, the microglia. Interactions between the growing family of B7 costimulatory ligands and their receptors are increasingly recognized as important pathways for costimulation and/or inhibition of immune responses.

Human and mouse microglial cells constitutively express B7 homolog 1 (B7-H1) in vitro. However, under inflammatory conditions [presence of interferon- (IFN-) or T-helper 1 supernatants], a significant upregulation of B7-H1 was detectable. Expression levels of B7-H1 protein on microglial cells were substantially higher compared with astrocytes or splenocytes. Coculture experiments of major histocompatibility complex class II-positive antigen-presenting cells (APC) with syngeneic T cells in the presence of antigen demonstrated the functional consequences of B7-H1 expression on T-cell activation. In the presence of a neutralizing anti-B7-H1 antibody, both the production of inflammatory cytokines (IFN- and interleukin-2) and the upregulation of activation markers (inducible costimulatory signal) by T cells were markedly enhanced. Interestingly, this effect was clearly more pronounced when microglial cells were used as APC, compared with astrocytes or splenocytes. Furthermore, B7-H1 was highly upregulated during the course of myelin oligodendrocyte glycoprotein-induced and proteolipid protein-induced experimental allergic encephalomyelitis in vivo. Expression was predominantly localized to areas of strongest inflammation and could be colocalized with microglial cells/macrophages as well as T cells.

Together, our data propose microglial B7-H1 as an important immune inhibitory molecule capable of downregulating T-cell activation in the CNS and thus confining immunopathological damage.

Key words: encephalomyelitis; glia; immunity; microglia; neuropathology; tolerance; costimulation

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Received July 31, 2004; revised January 5, 2005; accepted January 14, 2005.

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