scholarly journals Modulation of Major Histocompatibility Class II Protein Expression by Varicella-Zoster Virus

2000 ◽  
Vol 74 (4) ◽  
pp. 1900-1907 ◽  
Author(s):  
Allison Abendroth ◽  
Barry Slobedman ◽  
Eunice Lee ◽  
Elizabeth Mellins ◽  
Mark Wallace ◽  
...  
Keyword(s):  
Cell Surface ◽  
Varicella Zoster Virus ◽  
Mhc Class Ii ◽  
Class Ii ◽  
Northern Blot Hybridization ◽  
Major Histocompatibility ◽  
Varicella Zoster ◽  
Ifn Γ ◽  
In Cells

ABSTRACT We sought to investigate the effects of varicella-zoster virus (VZV) infection on gamma interferon (IFN-γ)-stimulated expression of cell surface major histocompatibility complex (MHC) class II molecules on human fibroblasts. IFN-γ treatment induced cell surface MHC class II expression on 60 to 86% of uninfected cells, compared to 20 to 30% of cells which had been infected with VZV prior to the addition of IFN-γ. In contrast, cells that were treated with IFN-γ before VZV infection had profiles of MHC class II expression similar to those of uninfected cell populations. Neither IFN-γ treatment nor VZV infection affected the expression of transferrin receptor (CD71). In situ and Northern blot hybridization of MHC II (MHC class II DR-α) RNA expression in response to IFN-γ stimulation revealed that MHC class II DR-α mRNA accumulated in uninfected cells but not in cells infected with VZV. When skin biopsies of varicella lesions were analyzed by in situ hybridization, MHC class II transcripts were detected in areas around lesions but not in cells that were infected with VZV. VZV infection inhibited the expression of Stat 1α and Jak2 proteins but had little effect on Jak1. Analysis of regulatory events in the IFN-γ signaling pathway showed that VZV infection inhibited transcription of interferon regulatory factor 1 and the MHC class II transactivator. This is the first report that VZV encodes an immunomodulatory function which directly interferes with the IFN-γ signal transduction via the Jak/Stat pathway and enables the virus to inhibit IFN-γ induction of cell surface MHC class II expression. This inhibition of MHC class II expression on VZV-infected cells in vivo may transiently protect cells from CD4+ T-cell immune surveillance, facilitating local virus replication and transmission during the first few days of cutaneous lesion formation.

scholarly journals Complex Formation Facilitates Endocytosis of the Varicella-Zoster Virus gE:gI Fc Receptor

1998 ◽  
Vol 72 (2) ◽  
pp. 1542-1551 ◽  
Author(s):  
Julie K. Olson ◽  
Charles Grose
Keyword(s):  
Steady State ◽  
Cell Surface ◽  
Varicella Zoster Virus ◽  
Surface Protein ◽  
Cytoplasmic Tail ◽  
Fc Receptor ◽  
Open Reading Frames ◽  
Major Constituent ◽  
Varicella Zoster ◽  
In Cells

ABSTRACT Open reading frames within the unique short segment of alphaherpesvirus genomes participate in egress and cell-to-cell spread. The case of varicella-zoster virus (VZV) is of particular interest not only because the virus is highly cell associated but also because its most prominent cell surface protein, gE, bears semblance to the mammalian Fc receptor FcγRII. A previous study demonstrated that when expressed alone in cells, VZV gE was endocytosed from the cell surface through a tyrosine localization motif in its cytoplasmic tail (J. K. Olson and C. Grose, J. Virol. 71:4042–4054, 1997). Since VZV gE is normally found in association with gI in the infected cell, the present study was directed at defining the trafficking of the VZV gE:gI protein complex. First, VZV gI underwent endocytosis and recycling when it was expressed alone in cells, and interestingly, VZV gI contained a methionine-leucine internalization motif in its cytoplasmic tail. Second, VZV gI was found by confocal microscopy to colocalize with VZV gE during endocytosis and recycling in cells. Third, by a quantitative internalization assay, VZV gE:gI was shown to undergo endocytosis more efficiently (steady state, 55 to 60%) than either gE alone (steady state, ∼32%) or gI alone (steady state, ∼45%). Further, examination of endocytosis-deficient mutant proteins demonstrated that VZV gI exerted a more pronounced effect than gE on internalization of the complex. Most importantly, therefore, these studies suggest that VZV gI behaves as an accessory component by facilitating the endocytosis of the major constituent gE and thereby modulating the trafficking of the entire cell surface gE:gI Fc receptor complex.

scholarly journals Modulation of Gamma Interferon-Induced Major Histocompatibility Complex Class II Gene Expression by Porphyromonas gingivalis Membrane Vesicles

2002 ◽  
Vol 70 (3) ◽  
pp. 1185-1192 ◽  
Author(s):  
Ratchapin Srisatjaluk ◽  
Girish J. Kotwal ◽  
Lawrence A. Hunt ◽  
David E. Justus
Keyword(s):  
Endothelial Cells ◽  
Major Histocompatibility Complex ◽  
Mhc Class Ii ◽  
Porphyromonas Gingivalis ◽  
Membrane Vesicles ◽  
Class Ii ◽  
Gamma Interferon ◽  
Major Histocompatibility ◽  
Histocompatibility Complex ◽  
Ifn Γ

ABSTRACT Gamma interferon (IFN-γ)-induced endothelial cells actively participate in initiating immune responses by interacting with CD4+ T cells via class II major histocompatibility complex (MHC) surface glycoproteins. Previously, Porphyromonas gingivalis membrane vesicles were shown to selectively inhibit IFN-γ-induced surface expression of HLA-DR molecules by human umbilical cord vascular endothelial cells. In this study, we demonstrated an absence of HLA-DRα mRNA from IFN-γ-induced cells in the presence of P. gingivalis membrane vesicles by using reverse transcriptase-PCR and Southern blotting. Vesicles also prevented transcription of the gene encoding class II transactivator, a transactivator protein required for IFN-γ-induced expression of MHC class II genes. In addition, the effects of vesicles on IFN-γ signal transduction involving Jak and Stat proteins were characterized by using immunoprecipitation and Western blot analyses. Jak1 and Jak2 proteins could not be detected in endothelial cells treated with membrane vesicles. Consequently, IFN-γ-induced phosphorylation of Jak1, Jak2, and Stat1α proteins was prevented. The class II-inhibitory effect of the membrane vesicles could be eliminated by heating vesicles at 100°C for 30 min or by treating them with a cysteine proteinase inhibitor. This indicates that the cysteine proteinases were most likely responsible for the absence of Jak proteins observed in vesicle-treated cells. The observed increased binding of radiolabeled IFN-γ to vesicle-treated cells suggests that vesicles may also modulate the IFN-γ interactions with the cell surface. However, no evidence was obtained demonstrating that vesicles affected the expression of IFN-γ receptors. Thus, P. gingivalis membrane vesicles apparently inhibited IFN-γ-induced MHC class II by disrupting the IFN-γ signaling transduction pathway. Vesicle-inhibited class II expression also occurred in other IFN-γ-inducible cells. This suggested that the ability of P. gingivalis membrane vesicles to modulate antigen presentation by key cells may be an important mechanism used by this particular bacterium to escape immunosurveillance, thereby favoring its colonization and invasion of host tissues.

scholarly journals Chlamydia Inhibits Interferon γ–inducible Major Histocompatibility Complex Class II Expression by Degradation of  Upstream Stimulatory Factor 1

1999 ◽  
Vol 189 (12) ◽  
pp. 1931-1938 ◽  
Author(s):  
Guangming Zhong ◽  
Tao Fan ◽  
Li Liu
Keyword(s):  
Major Histocompatibility Complex ◽  
Mhc Class Ii ◽  
Class Ii ◽  
Intercellular Adhesion Molecule ◽  
Major Histocompatibility ◽  
Upstream Stimulatory Factor ◽  
Intercellular Adhesion Molecule 1 ◽  
Histocompatibility Complex ◽  
Ifn Γ ◽  
Stimulatory Factor

We report that chlamydiae, which are obligate intracellular bacterial pathogens, can inhibit interferon (IFN)-γ–inducible major histocompatibility complex (MHC) class II expression. However, the IFN-γ–induced IFN regulatory factor-1 (IRF-1) and intercellular adhesion molecule 1 (ICAM-1) expression is not affected, suggesting that chlamydia may selectively target the IFN-γ signaling pathways required for MHC class II expression. Chlamydial inhibition of MHC class II expression is correlated with degradation of upstream stimulatory factor (USF)-1, a constitutively and ubiquitously expressed transcription factor required for IFN-γ induction of class II transactivator (CIITA) but not of  IRF-1 and ICAM-1. CIITA is an obligate mediator of IFN-γ–inducible MHC class II expression. Thus, diminished CIITA expression as a result of USF-1 degradation may account for the suppression of the IFN-γ–inducible MHC class II in chlamydia-infected cells. These results reveal a novel immune evasion strategy used by the intracellular bacterial pathogen chlamydia that improves our understanding of the molecular basis of pathogenesis.

scholarly journals Mycobacterium bovis BCG Urease Attenuates Major Histocompatibility Complex Class II Trafficking to the Macrophage Cell Surface

2004 ◽  
Vol 72 (7) ◽  
pp. 4200-4209 ◽  
Author(s):  
Khalid Sendide ◽  
Ala-Eddine Deghmane ◽  
Jean-Marc Reyrat ◽  
Amina Talal ◽  
Zakaria Hmama
Keyword(s):  
Major Histocompatibility Complex ◽  
Cell Surface ◽  
Major Histocompatibility Complex Class ◽  
Mycobacterium Bovis ◽  
Surface Expression ◽  
Class Ii ◽  
Complex Class ◽  
Major Histocompatibility ◽  
Histocompatibility Complex ◽  
Ifn Γ

ABSTRACT We have previously shown that Mycobacterium tuberculosis attenuates cell surface expression of major histocompatibility complex class II molecules in response to gamma interferon (IFN-γ) by a mechanism dependent on intracellular sequestration of α,β dimers. In this study we examined whether intracellular alkalinization due to mycobacterial urease could account for the defect in intracellular trafficking of class II molecules. Phagocytosis of wild-type Mycobacterium bovis BCG was associated with secretion of ammonia intracellularly, which increased substantially upon addition of exogenous urea to the culture medium. Increased intracellular ammonia, due to urea degradation by the bacterium, correlated with inhibition of class II surface expression. Conversely, no ammonia was detected in cells infected with a urease-negative mutant strain of M. bovis BCG, which also displayed a reduced effect on surface expression of class II molecules. A direct cause-effect relationship between urease and class II molecule trafficking was established with experiments where cells ingesting beads coated with purified urease showed an increased ammonia level and decreased surface expression of class II in response to IFN-γ. In contrast to BCG, infection of macrophages with Mycobacterium smegmatis, which expresses relatively greater urease activity in cell-free culture, had a marginal effect on both the intracellular level of ammonia and class II expression. The limited effect of M. smegmatis was consistent with a failure to resist intracellular killing, suggesting that urease alone is not sufficient to resist macrophage microbicidal mechanisms and that this is required for a more distal effect on cell regulation. Our results demonstrate that alkalinization of critical intracellular organelles by pathogenic mycobacteria expressing urease contributes significantly to the intracellular retention of class II dimers.

scholarly journals Involvement of CREB Binding Protein in Expression of Major Histocompatibility Complex Class II Genes via Interaction with the Class II Transactivator

1998 ◽  
Vol 18 (11) ◽  
pp. 6777-6783 ◽  
Author(s):  
Androniki Kretsovali ◽  
Theodora Agalioti ◽  
Charalambos Spilianakis ◽  
Eleni Tzortzakaki ◽  
Menie Merika ◽  
...  
Keyword(s):  
Major Histocompatibility Complex ◽  
Mhc Class Ii ◽  
Binding Protein ◽  
Class Ii ◽  
Creb Binding Protein ◽  
Major Histocompatibility ◽  
Class Ii Transactivator ◽  
Histocompatibility Complex ◽  
Essential Components ◽  
Ifn Γ

ABSTRACT The class II transactivator (CIITA) is a key regulatory factor that controls expression of the major histocompatibility complex (MHC) class II genes that are essential components for antigen presentation and thus regulation of the immune response. We show here that the adenovirus E1A protein interferes with the action of CIITA and inhibits both B-cell-specific and gamma interferon (IFN-γ)-induced expression of MHC class II promoters. Transfection studies provide evidence for the functional role of the CREB-binding protein (CBP) in IFN-γ and CIITA-mediated MHC class II promoter activation. We demonstrate that the N-terminally located transcription activation domain of CIITA physically interacts with both the N-terminal and the E1A-binding (C/H3) regions of CBP. These results suggest the involvement of a multisubunit complex, which contains the gene-specific coactivator CIITA and the versatile coactivator CBP, in MHC class II gene regulation, which may be responsible for both high-level expression and modulation by different signaling pathways.

Latent cytomegalovirus down-regulates major histocompatibility complex class II expression on myeloid progenitors

Blood ◽  
2002 ◽  
Vol 100 (8) ◽  
pp. 2867-2873 ◽  
Author(s):  
Barry Slobedman ◽  
Edward S. Mocarski ◽  
Ann M. Arvin ◽  
Elizabeth D. Mellins ◽  
Allison Abendroth
Keyword(s):  
Major Histocompatibility Complex ◽  
Cell Surface ◽  
Mhc Class I ◽  
Mhc Class Ii ◽  
Latent Infection ◽  
Class Ii ◽  
Class I ◽  
Viral Gene ◽  
Major Histocompatibility ◽  
Histocompatibility Complex

Following primary infection, human cytomegalovirus (CMV) establishes a lifelong latent infection in bone marrow–derived myeloid lineage cells. Although downmodulation of major histocompatibility complex (MHC) class I and class II protein levels occurs during active viral replication, little is known about the modulation of these proteins during latent infection. When analyzed by flow cytometry, latently infected adherent cells collected from granulocyte macrophage progenitor (GM-P) cultures exhibited a striking reduction in MHC class II antigen present on the cell surface starting very early after exposure to virus that continued for more than 2 weeks. In comparison, cell surface levels of the monocyte cell surface marker CD14 remained unaltered in these cells. A recombinant virus (RV798) lacking the virus genes US2-US11 retained the ability to downmodulate MHC class II levels during latent infection. Immunoblot and immunofluorescent antibody staining analyses showed that the reduction in MHC class II surface levels during latency was associated with a block in protein trafficking. HLA-DR was retained within cytoplasmic vesicles that also contained HLA-DM. Thus, downmodulation remained independent of all previously characterized MHC class I and class II immunomodulatory viral gene products and involved a mechanism not previously ascribed to any viral function. These data show that latent infection is accompanied by reduced cell surface expression of MHC class II proteins, a strategy that would afford the virus escape from immunosurveillance and increase the chances for lifelong latent infection.

Cell surface expression of the Varicella-zoster virus glycoproteins and Fc receptor

Virology ◽  
1990 ◽  
Vol 178 (1) ◽  
pp. 263-272 ◽  
Author(s):  
Virginia Litwin ◽  
Matyas Sandor ◽  
Charles Grose
Keyword(s):  
Cell Surface ◽  
Varicella Zoster Virus ◽  
Surface Expression ◽  
Fc Receptor ◽  
Cell Surface Expression ◽  
Varicella Zoster

scholarly journals Relationship between invariant chain expression and major histocompatibility complex class II transport into early and late endocytic compartments.

1993 ◽  
Vol 177 (3) ◽  
pp. 583-596 ◽  
Author(s):  
P Romagnoli ◽  
C Layet ◽  
J Yewdell ◽  
O Bakke ◽  
R N Germain
Keyword(s):  
Major Histocompatibility Complex ◽  
Mhc Class Ii ◽  
Class Ii ◽  
Endocytic Pathway ◽  
Invariant Chain ◽  
Major Histocompatibility ◽  
Histocompatibility Complex ◽  
Late Endosomes ◽  
Early Endosomes ◽  
Endocytic Compartments

Invariant chain (Ii), which associates with major histocompatibility complex (MHC) class II molecules in the endoplasmic reticulum, contains a targeting signal for transport to intracellular vesicles in the endocytic pathway. The characteristics of the target vesicles and the relationship between Ii structure and class II localization in distinct endosomal subcompartments have not been well defined. We demonstrate here that in transiently transfected COS cells expressing high levels of the p31 or p41 forms of Ii, uncleaved Ii is transported to and accumulates in transferrin-accessible (early) endosomes. Coexpressed MHC class II is also found in this same compartment. These early endosomes show altered morphology and a slower rate of content movement to later parts of the endocytic pathway. At more moderate levels of Ii expression, or after removal of a highly conserved region in the cytoplasmic tail of Ii, coexpressed class II molecules are found primarily in vesicles with the characteristics of late endosomes/prelysosomes. The Ii chains in these late endocytic vesicles have undergone proteolytic cleavage in the lumenal region postulated to control MHC class II peptide binding. These data indicate that the association of class II with Ii results in initial movement to early endosomes. At high levels of Ii expression, egress to later endocytic compartments is delayed and class II-Ii complexes accumulate together with endocytosed material. At lower levels of Ii expression, class II-Ii complexes are found primarily in late endosomes/prelysosomes. These data provide evidence that the route of class II transport to the site of antigen processing and loading involves movement through early endosomes to late endosomes/prelysosomes. Our results also reveal an unexpected ability of intact Ii to modify the structure and function of the early endosomal compartment, which may play a role in regulating this processing pathway.

scholarly journals CD1 and Major Histocompatibility Complex II Molecules Follow a Different Course during Dendritic Cell Maturation

2003 ◽  
Vol 14 (8) ◽  
pp. 3378-3388 ◽  
Author(s):  
Nicole N. van der Wel ◽  
Masahiko Sugita ◽  
Donna M. Fluitsma ◽  
Xaiochun Cao ◽  
Gerty Schreibelt ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Major Histocompatibility Complex ◽  
Dendritic Cell ◽  
Mhc Class Ii ◽  
Class Ii ◽  
Dendritic Cell Maturation ◽  
Cell Maturation ◽  
Major Histocompatibility ◽  
Mhc Molecules ◽  
Histocompatibility Complex

The maturation of dendritic cells is accompanied by the redistribution of major histocompatibility complex (MHC) class II molecules from the lysosomal MHC class II compartment to the plasma membrane to mediate presentation of peptide antigens. Besides MHC molecules, dendritic cells also express CD1 molecules that mediate presentation of lipid antigens. Herein, we show that in human monocyte-derived dendritic cells, unlike MHC class II, the steady-state distribution of lysosomal CD1b and CD1c isoforms was unperturbed in response to lipopolysaccharide-induced maturation. However, the lysosomes in these cells underwent a dramatic reorganization into electron dense tubules with altered lysosomal protein composition. These structures matured into novel and morphologically unique compartments, here termed mature dendritic cell lysosomes (MDL). Furthermore, we show that upon activation mature dendritic cells do not lose their ability of efficient clathrin-mediated endocytosis as demonstrated for CD1b and transferrin receptor molecules. Thus, the constitutive endocytosis of CD1b molecules and the differential sorting of MHC class II from lysosomes separate peptide- and lipid antigen-presenting molecules during dendritic cell maturation.

scholarly journals Varicella-Zoster Virus IE63, a Major Viral Latency Protein, Is Required To Inhibit the Alpha Interferon-Induced Antiviral Response

2007 ◽  
Vol 81 (15) ◽  
pp. 7844-7851 ◽  
Author(s):  
Aruna P. N. Ambagala ◽  
Jeffrey I. Cohen
Keyword(s):  
Varicella Zoster Virus ◽  
Melanoma Cells ◽  
Alpha Interferon ◽  
Parental Virus ◽  
Initiation Factor ◽  
Viral Gene ◽  
Α Subunit ◽  
Varicella Zoster ◽  
In Cells ◽  
Hsv 1

ABSTRACT Varicella-zoster virus (VZV) open reading frame 63 (ORF63) is the most abundant transcript expressed during latency in human sensory ganglia. VZV with ORF63 deleted is impaired for replication in melanoma cells and fibroblasts and for latency in rodents. We found that replication of the ORF63 deletion mutant is fully complemented in U2OS cells, which have been shown to complement the growth of herpes simplex virus type 1 (HSV-1) ICP0 mutants. Since HSV-1 ICP0 mutants are hypersensitive to alpha interferon (IFN-α), we examined the effect of IFN-α on VZV replication. Replication of the ORF63 mutant in melanoma cells was severely inhibited in the presence of IFN-α, in contrast to other VZV mutants that were similarly impaired for replication or to parental virus. The VZV ORF63 mutant was not hypersensitive to IFN-γ. IFN-α inhibited viral-gene expression in cells infected with the ORF63 mutant at a posttranscriptional level. Since IFN-α stimulates gene products that can phosphorylate the α subunit of eukaryotic initiation factor 2 (eIF-2α) and inhibit translation, we determined whether cells infected with the ORF63 mutant had increased phosphorylation of eIF-2α compared with cells infected with parental virus. While phosphorylated eIF-2α was undetectable in uninfected cells or cells infected with parental virus, it was present in cells infected with the ORF63 mutant. Conversely, expression of IE63 (encoded by ORF63) in the absence of other viral proteins inhibited phosphorylation of eIF-2α. Since IFN-α has been shown to limit VZV replication in human skin xenografts, the ability of VZV IE63 to block the effects of the cytokine may play a critical role in VZV pathogenesis.

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