Human Cytomegalovirus Infection of Immature Dendritic Cells and Macrophages

Jahn, Gerhard; Stenglein, S.; Riegler, Susanne; Einsele, Hermann; Sinzger, Christian

doi:10.1159/000053973

Cited by 40 publications

(36 citation statements)

References 29 publications

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“…In contrast, IDO has been involved in the regulatory function of DCs (32). Because HCMV can infect DCs (45), regulatory functions of DCs may be perturbed by down-regulation of IFN-␥-inducible IDO. Constitutive IDO is essential in the maintenance of pregnancy (46).…”

Section: Cd4mentioning

confidence: 99%

Inhibition of IFN-γ-Induced STAT1 Tyrosine Phosphorylation by Human CMV Is Mediated by SHP2

Baron

Davignon

2008

The Journal of Immunology

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Human CMV (HCMV) is a ubiquitous β-herpesvirus which has developed several mechanisms of escape from the immune system. IFN-γ-induced signaling relies on the integrity of the JAK/STAT pathway which is regulated by phosphorylation steps and leads to nuclear translocation of tyrosine-phosphorylated STAT1 (STAT1-P-Tyr), and its binding to IFN-γ activation site sequences of IFN-γ-inducible promoters. Activation of those promoters leads to the expression of genes involved in the immune response and in the antiviral effects of IFN-γ. Src homology region 2 domain-containing phosphatase 2 (SHP2) is a ubiquitous phosphatase involved in the regulation of IFN-γ-mediated tyrosine phosphorylation. Several mechanisms account for the inhibition IFN-γ signaling pathway by HCMV. In this study, we have identified a new mechanism that involved the inhibition of STAT1 tyrosine phosphorylation within 12–24 h postinfection. This defect was dependent on HCMV transcription. Consequences were impaired nuclear translocation of STAT1-P-Tyr, inhibition of IFN-γ activation site-STAT1 interaction, and inhibition of HLA-DR expression. Expression of indoleamine-2,3-dioxygenase which is involved in the antiviral effects of IFN-γ was also inhibited. Treatment of cells with sodium orthovanadate rescued STAT1 tyrosine phosphorylation, suggesting that a tyrosine phosphatase was involved in this inhibition. Coimmunoprecipitation of STAT1 and SHP2 was induced by HCMV infection, and SHP2 small interfering RNA restored the expression of STAT1-P-Tyr. Our data suggest that SHP2 activation induced by HCMV infection is responsible for the down-regulation of IFN-γ-induced STAT1 tyrosine phosphorylation.

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Section: Cd4mentioning

confidence: 99%

Inhibition of IFN-γ-Induced STAT1 Tyrosine Phosphorylation by Human CMV Is Mediated by SHP2

Baron

Davignon

2008

The Journal of Immunology

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“…[15][16][17][18]24 However, a variety of cell lineages may be infected with CMV, and it is unknown if the inhibition of antigen presentation observed in fibroblasts in vitro is equivalent in all infected cells in vivo. 30,31 Studies of the specificity of the CD8 ϩ CTL response induced in mice by experimental inoculation with murine CMV identified CTL responses to CMV antigens that are not presented by cells infected with wild-type CMV due to viral interference with class I antigen presentation. [32][33][34][35] In humans, Elispot assays with synthetic peptides selected from 14 human CMV proteins identified in some donors a significant response to pp50 in addition to pp65 and IE-1, and a low frequency response to peptides from US2, US3, US6, US11, UL16, and UL18, which have not previously been identified as target antigens.…”

Section: Introductionmentioning

confidence: 99%

Immune evasion proteins of human cytomegalovirus do not prevent a diverse CD8+ cytotoxic T-cell response in natural infection

Manley

Luy

Jones

et al. 2004

Blood

100

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Although cytomegalovirus (CMV) expresses proteins that interfere with antigen presentation by class I major histocompatibility complex (MHC) molecules, CD8 ؉ cytotoxic T cells (CTLs) are indispensable for controlling infection and maintaining latency. Here, a cytokine flow cytometry assay that employs fibroblasts infected with a mutant strain of CMV (RV798), which is deleted of the 4 viral genes that are responsible for interfering with class I MHC presentation, was used to examine the frequency and specificity of the CD8 ؉ CTLs to CMV in immunocompetent CMV-seropositive individuals. A large fraction of the CD8 ؉ CTL response was found to be specific for viral antigens expressed during the immediate early and early phases of virus replication and presented by fibroblasts infected with RV798 but not wild-type CMV. These results demonstrate that the inhibition of class I antigen presentation observed in CMV-infected cells in vitro is not sufficient to prevent the induction of a broad repertoire of CD8 ؉ CTLs after natural infection in vivo. Thus, reconstitution of T-cell immunity in immunodeficient patients by cell therapy or by vaccination may need to target multiple viral antigens to completely restore immunologic control of

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“…HCMV decreases cell-surface MHC class II expression in infected dendritic cells (62)(63)(64) and monocyte/macrophages, which are major targets of HCMV infection, latency, and reactivation (32,65,66). Interestingly, multiple mechanisms appear to mediate this decrease (64 -66).…”

Section: Discussionmentioning

confidence: 99%

Human Cytomegalovirus Disrupts Constitutive MHC Class II Expression

Cebulla

Miller

Zhang

et al. 2002

The Journal of Immunology

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CD8+ and CD4+ T lymphocytes are important in controlling human CMV (HCMV) infection, but the virus has evolved protean mechanisms to inhibit MHC-based Ag presentation and escape T lymphocyte immunosurveillance. Herein, the interaction of HCMV with the MHC class II Ag presentation pathway was investigated in cells stably transfected with class II transactivator. Flow cytometry experiments demonstrate that HCMV infection decreases cell-surface MHC class II expression. HCMV down-regulates MHC class II surface expression without a significant effect on class II RNA or steady-state protein levels. SDS-stability and confocal microscopy experiments demonstrate normal levels of steady-state peptide-loaded class II molecules in infected cells and that class II molecules reach late endosomal and HLA-DM positive peptide-loading compartments. However, MHC class II positive vesicles are retained in an abnormal perinuclear distribution. Finally, experiments with a mutant HCMV strain demonstrate that this novel mechanism of decreased MHC class II expression is not mediated by one of the known HCMV immunomodulatory genes. These defects in MHC class II expression combined with previously identified CMV strategies for decreasing MHC class I expression enables infected cells to evade T lymphocyte immunosurveillance.

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Human Cytomegalovirus Infection of Immature Dendritic Cells and Macrophages

Cited by 40 publications

References 29 publications

Inhibition of IFN-γ-Induced STAT1 Tyrosine Phosphorylation by Human CMV Is Mediated by SHP2

Inhibition of IFN-γ-Induced STAT1 Tyrosine Phosphorylation by Human CMV Is Mediated by SHP2

Immune evasion proteins of human cytomegalovirus do not prevent a diverse CD8+ cytotoxic T-cell response in natural infection

Human Cytomegalovirus Disrupts Constitutive MHC Class II Expression

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