Peripheral dendritic cells are essential for both the innate and adaptive antiviral immune responses in the central nervous system

Steel, Christina; Hahto, Suzanne M.; Ciavarra, Richard P.

doi:10.1016/j.virol.2009.01.032

Cited by 31 publications

(48 citation statements)

References 69 publications

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“…Moreover, there is increasing evidence supporting a role for glial cells in modulating synaptic transmission, and NMDAR-mediated currents in particular (35,36). In addition to being expressed by neurons, low levels of MHCI molecules are present on astrocytes and microglia in healthy brains (37,38). Therefore, it is possible that MHCI regulates NMDARs through neuron-glia interactions.…”

Section: Discussionmentioning

confidence: 99%

MHC class I modulates NMDA receptor function and AMPA receptor trafficking

Fourgeaud¹,

Davenport²,

Tyler

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Proteins of the major histocompatibility complex class I (MHCI) are known for their role in immunity and have recently been implicated in long-term plasticity of excitatory synaptic transmission. However, the mechanisms by which MHCI influences synaptic plasticity remain unknown. Here we show that endogenous MHCI regulates synaptic responses mediated by NMDA-type glutamate receptors (NMDARs) in the mammalian central nervous system (CNS). The AMPA/NMDA ratio is decreased at MHCI-deficient hippocampal synapses, reflecting an increase in NMDAR-mediated currents. This enhanced NMDAR response is not associated with changes in the levels, subunit composition, or gross subcellular distribution of NMDARs. Increased NMDAR-mediated currents in MHCI-deficient neurons are associated with characteristic changes in AMPA receptor trafficking in response to NMDAR activation. Thus, endogenous MHCI tonically inhibits NMDAR function and controls downstream NMDAR-induced AMPA receptor trafficking during the expression of plasticity.immune | GluR | hippocampus P roteins of the major histocompatibility complex class I (MHCI) are best known for their role in adaptive immunity, but several lines of evidence suggest they also have nonimmune functions in neurons (1, 2). MHCI is expressed by healthy neurons in the developing and adult CNS (3-7). Neuronal MHCI mRNA levels are dynamic during development and are regulated by electrical activity (3, 4) and by the cAMP-response element-binding protein (CREB) (8). MHCI protein is enriched in synaptic fractions (4) and is detected in hippocampal dendritic spines, where it colocalizes with PSD-95 (9).Studies in mice genetically deficient for cell-surface MHCI (β2m −/− TAP −/− mice) suggest a role for MHCI in activity-dependent plasticity. In MHCI-deficient mice, NMDA receptor (NMDAR)-dependent hippocampal long-term potentiation (LTP) is enhanced, whereas long-term depression (LTD) is abolished (4). Although the mechanisms by which MHCI mediates immune signaling have been relatively well characterized, nothing is known about how MHCI contributes to NMDAR-dependent plasticity in vitro or in vivo.In the adult hippocampus, plasticity induced by activation of NMDARs is expressed as changes in the trafficking and function of AMPA receptors (AMPARs) (10-13). In current models, the magnitude and kinetics of NMDAR activation determine whether potentiation or depression is induced, with large, transient NMDAR activation causing LTP and smaller, longer-lasting activation causing LTD (14, 15). Therefore, to better understand the role of endogenous MHCI in the induction or expression of synaptic plasticity, we examined the levels, distribution, trafficking, and function of AMPA-and NMDA-type receptors in MHCI-deficient hippocampal neurons.The current experiments reveal an unexpected role for postsynaptic MHCI in controlling NMDAR function. Loss of MHCI causes a drop in the AMPA/NMDA ratio and an enhancement of NMDAR-mediated responses at CA3-CA1 synapses. This enhancement cannot be attributed to changes in th...

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Section: Discussionmentioning

confidence: 99%

MHC class I modulates NMDA receptor function and AMPA receptor trafficking

Fourgeaud¹,

Davenport²,

Tyler

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…Moreover, despite a lack of typical lymph drainage, DCs from the brain appear to acquire antigens there and migrate to the cervical lymph nodes to initiate CD8 + T-cell responses, which is well documented, for example, for neuroinflammatory conditions (Karman et al , 2004a, 2004b; Hatterer et al , 2008; Steel et al , 2009). However, little is known about such mechanisms in GB and about the influence of ALA/PDT treatment of gliomas on the afferent phase of adaptive immunity.…”

mentioning

confidence: 99%

Heat-shock protein 70-dependent dendritic cell activation by 5-aminolevulinic acid-mediated photodynamic treatment of human glioblastoma spheroids in vitro

et al. 2011

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Background:T-cell responses contribute to the anti-tumoural effect of photodynamic therapy (PDT). For such responses to occur, dendritic cells (DCs) have to migrate to the tumour, take up tumour antigens and respond to danger signals with maturation, before they engage in T-cell activation. Here, we have studied the effect of 5-aminolevulinic acid (ALA)-mediated PDT on DCs in vitro in a human spheroid model of glioblastoma (GB).Methods:Spheroids of the GB cell lines U87 and U251 were treated with ALA/PDT, and effects on attraction, uptake of tumour antigens and maturation of DCs were studied. To block heat-shock protein-70 (HSP-70) on the spheroids, neutralising antibodies were used.Results:5-Aminolevulinic acid /PDT-treated GB spheroids attracted DCs that acquired tumour antigens from the spheroids effectively. Moreover, co-culture with ALA/PDT-treated spheroids induced DC maturation as indicated by the upregulation of CD83 and co-stimulatory molecules as well as increased T-cell stimulatory activity of the DCs. Heat-shock protein-70 was upregulated on the spheroids after ALA/PDT treatment. Uptake of tumour antigens and DC maturation induced by the ALA/PDT-treated spheroids were inhibited when HSP-70 was blocked.Conclusion:ALA/PDT treatment of glioma spheroids promotes the three initial steps of the afferent phase of adaptive immunity, which is at least partially mediated by HSP-70.

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“…The only resident cells within the CNS parenchyma that can funct ion to any great extent as APCs are microglial cel ls, which represent 10-20% of the bra in parenchyma (Hickey and Kimura, 1988; Pedemonte et al, 2006; Steel et al, 2009). DCs, though not present under steady-state conditions, can be recruited into the inflamed CNS parenchyma from the periphery, most likely through the interactions of chemokine ligands and receptors (Pedemonte et al ., 2006).…”

Section: Adaptive Immune Response: Inside the Cnsmentioning

confidence: 99%

“…DCs, though not present under steady-state conditions, can be recruited into the inflamed CNS parenchyma from the periphery, most likely through the interactions of chemokine ligands and receptors (Pedemonte et al ., 2006). Peripheral DCs have been shown to play an important role in both the accumulation of clonally expanded CDS + virus-specific T cells within the CNS and in viral clearance from the CNS during viral encephalitis (Steel et al, 2009). It is somewhat controversial as to whether APCs bearing antigen can m igrate out of the CNS parenchyma to the cervical lymph nodes.…”

Section: Adaptive Immune Response: Inside the Cnsmentioning

confidence: 99%

“…ThereCD4+ T cells function mainly in a helper capacity within the CNS, as opposed to having any direct antiviral (Savarin and Bergmann, 2008). Cells of the CNS that can upregulate the expression of MHC class I and .are therefore potential infected targets for CD8 + CTLs include astrocytes, neurons (Kang and McGavern, 2009), and microglial cells (Steel et al, 2009). Therefore, CD8+ CTLs function as the primary mediators of the adaptive immune response in reducing viral replication within the CNS (Savarin and Bergmann, 2008).…”

Section: Once In the Cnsmentioning

confidence: 99%

See 1 more Smart Citation

Adaptive immune response to viral infections in the central nervous system

Libbey

Fujinami

2014

Handbook of Clinical Neurology

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Historically, the central nervous system (CNS) has been considered to be an immunologically privileged site within the body (Bailey et al., 2006; Galea et al. 2007; Engelhardt, 2008; Prendergast and Anderton, 2009). By definition, immunologically privileged sites, to include the brain, cornea, testis, and pregnant uterus, have a reduced/delayed ability to reject foreign tissue grafts compared to conventional sites within the body, such as skin (Streilein, 2003; Bailey et al., 2006; Carson et al., 2006; Mrass and Weninger, 2006; Kaplan and Niederkorn, 2007). In addition and conversely, tissue grafts prepared from immunologically privileged sites have increased survival, compared to tissue grafts prepared from conventional sites, when implanted at conventional sites (Streilein, 2003). The imune privilege of the CNS has been shown to be confined to the parenchyma, whereas the immune reactivity of the meninges and the ventricles, containing the choroid plexus, cerebrospinal fluid (CSF), and the circumventricular organs, is similar to conventionalsites (Carson et al., 2006; Engelhardt, 2006; Galea et al., 2007). This confinement of the imm une privilege to the parenchyma has also been demonstrated for experimental influenza virus infection in which confinement of the infection to the brain parenchyma did not result in efficient immune system priming whereas infection of the CSF elicited a virus-specific immune response comparable to that of intranasal infection (Stevenson et al. 1997). An important functional aspect of immune privilege is that damage due to the immune response and inflammation is limited within sensitive organs containing cell types that regenerate poorly, such as neurons within the brain (Mrass and Weninger, 2006; Galea et al.. 2007; Kaplan and Niederkorn, 2007).

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Peripheral dendritic cells are essential for both the innate and adaptive antiviral immune responses in the central nervous system

Cited by 31 publications

References 69 publications

MHC class I modulates NMDA receptor function and AMPA receptor trafficking

MHC class I modulates NMDA receptor function and AMPA receptor trafficking

Heat-shock protein 70-dependent dendritic cell activation by 5-aminolevulinic acid-mediated photodynamic treatment of human glioblastoma spheroids in vitro

Adaptive immune response to viral infections in the central nervous system

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