Cytomegalovirus infection and interferon-γ modulate major histocompatibility complex class I expression on neural stem cells

Cheeran, Maxim C.-J.; Jiang, Zibing; Hu, Shuxian; Ni, Hsiao Tzu; Palmquist, Joseph M.; Lokensgard, James R.

doi:10.1080/13550280802356845

Cited by 15 publications

(23 citation statements)

References 39 publications

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“…Luo et al [23] showed that HCMV infection in primary NPCs reduced the expression of Nestin, suggesting that HCMV affects the differentiation potential of NPCs. Similar results were also obtained from experiments with mouse NSCs infected with MCMV [10,13,24]. Those previous findings obtained from experiments with primary cultures of brain-derived neural cells were thus mostly reproduced in our experiments using NSPC/iPSCs.…”

Section: Discussionsupporting

confidence: 90%

Human cytomegalovirus induces apoptosis in neural stem/progenitor cells derived from induced pluripotent stem cells by generating mitochondrial dysfunction and endoplasmic reticulum stress

et al. 2013

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BackgroundCongenital human cytomegalovirus (HCMV) infection, a leading cause of birth defects, is most often manifested as neurological disorders. The pathogenesis of HCMV-induced neurological disorders is, however, largely unresolved, primarily because of limited availability of model systems to analyze the effects of HCMV infection on neural cells.MethodsAn induced pluripotent stem cell (iPSC) line was established from the human fibroblast line MRC5 by introducing the Yamanaka’s four factors and then induced to differentiate into neural stem/progenitor cells (NSPCs) by dual inhibition of the SMAD signaling pathway using Noggin and SB-431542.ResultsiPSC-derived NSPCs (NSPC/iPSCs) were susceptible to HCMV infection and allowed the expression of both early and late viral gene products. HCMV-infected NSPC/iPSCs underwent apoptosis with the activation of caspase-3 and −9 as well as positive staining by the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL). Cytochrome c release from mitochondria to cytosol was observed in these cells, indicating the involvement of mitochondrial dysfunction in their apoptosis. In addition, phosphorylation of proteins involved in the unfolded protein response (UPR), such as PKR-like eukaryotic initiation factor 2a kinase (PERK), c-Jun NH2-terminal kinase (JNK), inositol-requiring enzyme 1 (IRE1), and the alpha subunit of eukaryotic initiation factor 2 (eIF2α) was observed in HCMV-infected NSPC/iPSCs. These results, coupled with the finding of increased expression of mRNA encoding the C/EBP-homologous protein (CHOP) and the detection of a spliced form of X-box binding protein 1 (XBP1) mRNA, suggest that endoplasmic reticulum (ER) stress is also involved in HCMV-induced apoptosis of these cells.ConclusionsiPSC-derived NSPCs are thought to be a useful model to study HCMV neuropathogenesis and to analyze the mechanisms of HCMV-induced apoptosis in neural cells.

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Section: Discussionsupporting

confidence: 90%

Human cytomegalovirus induces apoptosis in neural stem/progenitor cells derived from induced pluripotent stem cells by generating mitochondrial dysfunction and endoplasmic reticulum stress

et al. 2013

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“…Studies on the effect of various concentrations of IFN-γ have indicated that higher concentrations of IFN-γ may activate caspases and potentially induce NSC apoptosis [37]. Previous studies in our lab have shown that at low concentration, IFN-γ can inhibit NSC proliferating without inducing apoptosis [59]. In the present study, we show that at the ratios of T-cells tested, NSC proliferation is suppressed without the overt induction of apoptosis.…”

Section: Discussionsupporting

confidence: 64%

“…Previous studies from our laboratory have shown that IFN-γ, a T-cell cytokine, inhibits murine NSC proliferation [32]. To determine if IFN-γ was produced by CD8 T-cells when stimulated in co-culture with NSCs, cytokine levels were measured from culture supernatants by capture ELISA method.…”

Section: Resultsmentioning

confidence: 99%

“…Our laboratory has demonstrated that the inflammatory response to HSV-1 infection clears virus from the brain, but leaves in its wake a chronic activated T [29], [30] and B lymphocyte [31] response, potentially serving critical surveillance functions. Persistent cytotoxic CD8 T-cells produce IFN-γ, a cytokine that both our laboratory and others have shown to alter NSC functions [32]. While a substantial number of studies have investigated the role of the inflammatory response in defense of and damage to the brain, little if anything is known about the impact of neuroimmune responses on NSCs in the context of viral encephalitis.…”

Section: Introductionmentioning

confidence: 98%

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Activated CD8+ T Lymphocytes Inhibit Neural Stem/Progenitor Cell Proliferation: Role of Interferon-Gamma

Rotschafer²,

Lokensgard

et al. 2014

PLoS ONE

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The ability of neural stem/progenitor cells (NSCs) to self-renew, migrate to damaged sites, and differentiate into neurons has renewed interest in using them in therapies for neurodegenerative disorders. Neurological diseases, including viral infections of the brain, are often accompanied by chronic inflammation, whose impact on NSC function remains unexplored. We have previously shown that chronic neuroinflammation, a hallmark of experimental herpes simplex encephalitis (HSE) in mice, is dominated by brain-infiltrating activated CD8 T-cells. In the present study, activated CD8 lymphocytes were found to suppress NSC proliferation profoundly. Luciferase positive (luc+) NSCs co-cultured with activated, MHC-matched, CD8+ lymphocytes (luc−) showed two- to five-fold lower luminescence than co-cultures with un-stimulated lymphocytes. On the other hand, similarly activated CD4+ lymphocytes did not suppress NSC growth. This differential lymphocyte effect on proliferation was confirmed by decreased BrdU uptake by NSC cultured with activated CD8 T-cells. Interestingly, neutralizing antibodies to interferon-gamma (IFN-γ) reversed the impact of CD8 lymphocytes on NSCs. Antibodies specific to the IFN-γ receptor-1 subunit complex abrogated the inhibitory effects of both CD8 lymphocytes and IFN-γ, indicating that the inhibitory effect of these cells was mediated by IFN-γ in a receptor-specific manner. In addition, activated CD8 lymphocytes decreased levels of nestin and Sox2 expression in NSCs while increasing GFAP expression, suggesting possible induction of an altered differentiation state. Furthermore, NSCs obtained from IFN-γ receptor-1 knock-out embryos were refractory to the inhibitory effects of activated CD8+ T lymphocytes on cell proliferation and Sox2 expression. Taken together, the studies presented here demonstrate a role for activated CD8 T-cells in regulating NSC function mediated through the production of IFN-γ. This cytokine may influence neuro-restorative processes and ultimately contribute to the long-term sequelae commonly seen following herpes encephalitis.

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“…Our previous in vivo studies have shown that subsequent to intracerebroventricular (icv) infection with MCMV, in immunocompetent animals, viral brain infection is localized primarily to cells that line the periventricular region. These periventricular target cells were subsequently identified as nestin-positive, neural stem cells [9]. Infection spreads to astrocytes within the brain parenchyma only in the absence of an effective CD8 + T cell response [10].…”

Section: Introductionmentioning

confidence: 99%

Glial cell activation, recruitment, and survival of B-lineage cells following MCMV brain infection

Lokensgard

Mutnal

Prasad

et al. 2016

J Neuroinflammation

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BackgroundChemokines produced by reactive glia drive migration of immune cells and previous studies from our laboratory have demonstrated that CD19+ B cells infiltrate the brain. In this study, in vivo and in vitro experiments investigated the role of reactive glial cells in recruitment and survival of B-lineage cells in response to (murine cytomegalovirus) MCMV infection.MethodsFlow cytometric analysis was used to assess chemokine receptor expression on brain-infiltrating B cells. Real-time RT-PCR and ELISA were used to measure chemokine levels. Dual-immunohistochemical staining was used to co-localize chemokine production by reactive glia. Primary glial cell cultures and migration assays were used to examine chemokine-mediated recruitment. Astrocyte: B cell co-cultures were used to investigate survival and proliferation.ResultsThe chemokine receptors CXCR3, CXCR5, CCR5, and CCR7 were detected on CD19+ cells isolated from the brain during MCMV infection. In particular, CXCR3 was found to be elevated on an increasing number of cells over the time course of infection, and it was the primary chemokine receptor expressed at 60 days post infection Quite different expression kinetics were observed for CXCR5, CCR5, and CCR7, which were elevated on the highest number of cells early during infection and decreased by 14, 30, and 60 days post infection Correspondingly, elevated levels of CXCL9, CXCL10, and CXCL13, as well as CCL5, were found within the brains of infected animals, and only low levels of CCL3 and CCL19 were detected. Differential expression of CXCL9/CXCL10 and CXCL13 between microglia and astrocytes was apparent, and B cells moved towards supernatants from MCMV-infected microglia, but not astrocytes. Pretreatment with neutralizing Abs to CXCL9 and CXCL10 inhibited this migration. In contrast, neutralizing Abs to the ligand of CXCR5 (i.e., CXCL13) did not significantly block chemotaxis. Proliferation of brain-infiltrating B cells was detected at 7 days post infection and persisted through the latest time tested (60 days post infection). Finally, astrocytes produce BAFF (B cell activating factor of the TNF family) and promote proliferation of B cells via cell-to-cell contact.ConclusionsCXCR3 is the primary chemokine receptor on CD19+ B cells persisting within the brain, and migration to microglial cell supernatants is mediated through this receptor. Correspondingly, microglial cells produce CXCL9 and CXCL10, but not CXCL13. Reactive astrocytes promote B cell proliferation.

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Cytomegalovirus infection and interferon-γ modulate major histocompatibility complex class I expression on neural stem cells

Cited by 15 publications

References 39 publications

Human cytomegalovirus induces apoptosis in neural stem/progenitor cells derived from induced pluripotent stem cells by generating mitochondrial dysfunction and endoplasmic reticulum stress

Human cytomegalovirus induces apoptosis in neural stem/progenitor cells derived from induced pluripotent stem cells by generating mitochondrial dysfunction and endoplasmic reticulum stress

Activated CD8+ T Lymphocytes Inhibit Neural Stem/Progenitor Cell Proliferation: Role of Interferon-Gamma

Glial cell activation, recruitment, and survival of B-lineage cells following MCMV brain infection

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