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

Magnus, Tim; Schreiner, Bettina; Korn, Thomas; Jack, Carolyn; Guo, Hong; Antel, Jack P.; Ifergan, Igal; Chen, Lieping; Bischof, Felix; Bar‐Or, Amit; Wiendl, Heinz

doi:10.1523/jneurosci.4794-04.2005

Cited by 144 publications

(147 citation statements)

References 63 publications

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“…Importantly, similarly to our study, they also found this phenotype to persist in the recovery phase. Interestingly, the only co-stimulatory molecule being strongly regulated during demyelination and remyelination was Cd247 (B7-H1), a known inhibitory co-stimulatory molecule (Keir et al, 2008;Magnus et al, 2005;Ortler et al, 2008). Its expression was already induced at 2WD and remained upregulated during remyelination.…”

Section: Discussionmentioning

confidence: 99%

Identification of a microglia phenotype supportive of remyelination

Olah

Amor

Brouwer

et al. 2011

Glia

307

270

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In multiple sclerosis, endogenous oligodendrocyte precursor cells (OPCs) attempt to remyelinate areas of myelin damage. During disease progression, however, these attempts fail. It has been suggested that modulating the inflammatory environment of the lesion might provide a promising therapeutic approach to promote endogenous remyelination. Microglia are known to play a central role in neuroinflammatory processes. To investigate the microglia phenotype that supports remyelination, we performed genome-wide gene expression analysis of microglia from the corpus callosum during demyelination and remyelination in the mouse cuprizone model, in which remyelination spontaneously occurs after an episode of toxin-induced primary demyelination. We provide evidence for the existence of a microglia phenotype that supports remyelination already at the onset of demyelination and persists throughout the remyelination process. Our data show that microglia are involved in the phagocytosis of myelin debris and apoptotic cells during demyelination. Furthermore, they express a cytokine and chemokine repertoire enabling them to activate and recruit endogenous OPCs to the lesion site and deliver trophic support during remyelination. This study not only provides a detailed transcriptomic analysis of the remyelinationsupportive microglia phenotype but also reinforces the notion that the primary function of microglia is the maintenance of tissue homeostasis and the support of regeneration already at the earliest stages in the development of demyelinating lesions. V

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Section: Discussionmentioning

confidence: 99%

Identification of a microglia phenotype supportive of remyelination

Olah

Amor

Brouwer

et al. 2011

Glia

307

270

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“…PD-1, its receptor, is predominantly found on activated T and B cells [38,40,41]. Both PD-1 and B7-H1 are up-regulated during EAE and their expression has been shown to be correlated with the course of the disease [22,29,30]. B7-H1/PD-1 interactions are critically involved in the modulation of experimental autoimmune encephalomyelitis.…”

Section: Discussionmentioning

confidence: 99%

“…Recent data from human and murine studies suggest, that the B7-H1/PD-1 pathway seems to be critically involved in limiting parenchymal inflammation [22][23][24]. Using an animal model of diabetes, Martin-Orozco et al [25] elegantly demonstrated that parenchymal B7-H1 contributes to the limitation of insulitis and the resolution of inflammation.…”

Section: Introductionmentioning

confidence: 99%

“…In the murine CNS, B7-H1 expression is very limited under normal conditions. During inflammation, B7-H1 is significantly up-regulated by various CNS cells, including microglial cells [22,[28][29][30][31]. Microglial B7-H1 is inhibitory for encephalitogenic T cells thus fueling the hypothesis that inducible expression of inhibitory B7-H1 may counterbalance parenchymal inflammation [22].…”

Section: Introductionmentioning

confidence: 99%

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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

et al. 2008

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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-c/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.

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“…B7-H1 is constitutively expressed on different immune cells and can be inducibly expressed on many parenchymal cells (14)(15)(16)(17)(18) is crucially involved in maintenance of immunological tolerance (19,20). PD-1 has been identified as the canonical receptor for B7-H1 and is inducibly expressed on activated lymphocytes (21).…”

mentioning

confidence: 99%

B7-H1 Selectively Controls TH17 Differentiation and Central Nervous System Autoimmunity via a Novel Non–PD-1–Mediated Pathway

Herold

Posevitz

Chudyka

et al. 2015

The Journal of Immunology

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It is currently acknowledged that TH17 cells are critically involved in the pathogenesis of autoimmune diseases such as multiple sclerosis (MS). In this article, we demonstrate that signals delivered by the coinhibitory molecule B7-homologue 1 (B7-H1) via a B7-homologue 1 mouse-IgG2aFc (B7-H1-Ig) fusion protein nearly abolish TH17, but not TH1 and TH2, differentiation via direct interaction with the T cell. These effects were equally pronounced in the absence of programmed death-1 or B7.1 and B7.2 on the T cell side, thus providing clear evidence that B7-H1 modulates T cell differentiation via a novel receptor. Mechanistically, B7-H1 interfered with early TCR-mediated signaling and cytokine-mediated induction of the TH17-determining transcription factors retinoic acid-related orphan receptor γ t and IFN regulator factor-4 in a programmed death-1 and B7-independent fashion. In an animal model of MS, active myelin oligodendrocyte glycoprotein–induced experimental autoimmune encephalomyelitis, B7-H1-Ig exhibited a significant and long-lasting effect on disease severity upon administration during the first 5 d of the priming phase, which was accompanied by reduced TH17 responses in the periphery and within the CNS. Importantly, B7-H1-Ig was even capable of interfering with T cell encephalitogenicity when interaction with the T cells occurred after priming using an adoptive transfer experimental autoimmune encephalomyelitis model. In line with this, both naive human CD4+ T cells and differentiated TH17 effector cells from MS patients were highly sensitive toward B7-H1-Ig–mediated TH17 suppression. Together, we propose the existence of a novel B7-H1–mediated immune-regulatory pathway in T cells, which selectively limits murine and human TH17 cell responses and might be therapeutically exploited to control TH17-mediated autoimmunity.

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

Cited by 144 publications

References 63 publications

Identification of a microglia phenotype supportive of remyelination

Identification of a microglia phenotype supportive of remyelination

B7‐H1 restricts neuroantigen‐specific T cell responses and confines inflammatory CNS damage: Implications for the lesion pathogenesis of multiple sclerosis

B7-H1 Selectively Controls TH17 Differentiation and Central Nervous System Autoimmunity via a Novel Non–PD-1–Mediated Pathway

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