Cytomegalovirus selectively blocks antigen processing and presentation of its immediate–early gene product

Gilbert, Mark J.; Riddell, Stanley R.; Plachter, Bodo; Greenberg, Philip D.

doi:10.1038/383720a0

Cited by 248 publications

(150 citation statements)

References 26 publications

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“…Prior studies have suggested that pp65 is the primary target for HCMV-specific CD8 ϩ T cell responses (10,17,18,56), and that pp65 may inhibit the processing and presentation of IE1 (57). Our data suggest that infants are capable of generating IE1-specific CD8 ϩ T cell responses, and that IE1 may be more commonly targeted by CD8 ϩ T cells.…”

Section: Discussionsupporting

confidence: 51%

Human Cytomegalovirus Proteins pp65 and Immediate Early Protein 1 Are Common Targets for CD8+ T Cell Responses in Children with Congenital or Postnatal Human Cytomegalovirus Infection

Gibson

Piccinini²,

Lilleri³

et al. 2004

The Journal of Immunology

107

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Recombinant modified vaccinia Ankara- and peptide-based IFN-γ ELISPOT assays were used to detect and measure human CMV (HCMV)-specific CD8+ T cell responses to the pp65 (UL83) and immediate early protein 1 (IE1; UL123) gene products in 16 HCMV-infected infants and children. Age at study ranged from birth to 2 years. HCMV-specific CD8+ T cells were detected in 14 (88%) of 16 children at frequencies ranging from 60 to >2000 spots/million PBMC. Responses were detected as early as 1 day of age in infants with documented congenital infection. Nine children responded to both pp65 and IE1, whereas responses to pp65 or IE1 alone were detected in three and two children, respectively. Regardless of the specificity of initial responses, IE1-specific responses predominated by 1 year of age. Changes in HCMV epitopes targeted by the CD8+ T cell responses were observed over time; epitopes commonly recognized by HLA-A2+ adults with latent HCMV infection did not fully account for responses detected in early childhood. Finally, the detection of HCMV-specific CD8+ T cell responses was temporally associated with a decrease in peripheral blood HCMV load. Taken altogether, these data demonstrate that the fetus and young infant can generate virus-specific CD8+ T cell responses. Changes observed in the protein and epitope-specificity of HCMV-specific CD8+ T cells over time are consistent with those observed after other primary viral infections. The temporal association between the detection of HCMV-specific CD8+ T cell responses and the reduction in blood HCMV load supports the importance of CD8+ T cells in controlling primary HCMV viremia.

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Section: Discussionsupporting

confidence: 51%

Human Cytomegalovirus Proteins pp65 and Immediate Early Protein 1 Are Common Targets for CD8+ T Cell Responses in Children with Congenital or Postnatal Human Cytomegalovirus Infection

Gibson

Piccinini²,

Lilleri³

et al. 2004

The Journal of Immunology

107

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“…The CMV pp65-specific HLA-A2-restricted T cell clone ER1A3-3 (S. R. Riddell, unpublished data) was generated and maintained as described (17). Standard 4-h cytotoxicity assays with [ 51 Cr]sodium chromate-labeled target C1R-A2, C1R-A2-MICB, and C1R-A2-MICB-UL16 transfectants pulsed with titered concentrations of the specific pp65 NLVPMVATV peptide and the IFN-␥ and TNF-␣ release assays were carried out as described (6).…”

Section: T Cell Clones Cytotoxicity and Cytokine Release Assaysmentioning

confidence: 99%

“…C1R-MICB and C1R-MICB-UL16 cells stably transfected with a HLA-A2 cDNA construct were pulsed with titered concentrations of the CMV pp65 peptide and used as target and stimulator cells for the specific HLA-2-restricted CD8 ϩ CD28 Ϫ ␣␤ T cell clone ER 1A3-3 (Ref. 17 and S. R. Riddell, unpublished data). The results showed that under suboptimal peptide concentrations, T cell cytotoxicity declined more rapidly in the presence of UL16 (Fig.…”

Section: Effect Of Ul16 On Micb-dependent Nkg2d-mediated T Cell Activmentioning

confidence: 99%

Intracellular Retention of the MHC Class I-Related Chain B Ligand of NKG2D by the Human Cytomegalovirus UL16 Glycoprotein

Chalupny

Manley

et al. 2003

The Journal of Immunology

Self Cite

125

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Infection by human CMV induces expression of the cellular MHC class I-related chain A (MICA) and chain B (MICB) surface proteins, which function as ligands for the activating NKG2D receptor. Engagement of NKG2D triggers NK cells and costimulates Ag-specific effector CD8 αβ T cells. The potency of MHC class I-related chain-NKG2D in stimulating these anti-viral immune responses may be countered by a CMV-encoded transmembrane glycoprotein, UL16, which specifically binds MICB as well as two of the UL16-binding proteins that are ligands of NKG2D. However, the function and significance of these interactions are undefined. Using a stably transfected B cell line, we show that expression of UL16 results in loss of surface MICB. This effect is caused by the failure of newly synthesized MICB to mature and transit the secretory pathway due to physical association with UL16. The intracellular retention of these protein complexes is mediated by a tyrosine-based motif in the cytoplasmic tail sequence of UL16, which determines localization to or retrieval from the trans-Golgi network. Deletion of this motif restores surface expression of MICB, whereas UL16 may be redirected to endosomal compartments. Predictably, the retention of MICB abrogates the stimulatory function of NKG2D. These results suggest a potential mechanism of viral immune evasion. However, this activity remains to be confirmed with CMV-infected fibroblasts or endothelial cells, in particular because MICB is normally coexpressed with MICA, which is not retained by UL16.

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“…To avoid immune recognition, intracellular microorganisms, including viruses [1], intracellular bacteria [2] and protozoan parasites [3][4][5][6], have evolved mechanisms which interfere with antigen presentation pathways. These mechanisms may be pivotal, especially for those pathogens causing persistent infections.…”

Section: Introductionmentioning

confidence: 99%

Down-regulation of MHC class II molecules and inability to up-regulate class I molecules in murine macrophages after infection withToxoplasma gondii

Lüder

Lang

Beuerle

et al. 1998

Clinical and Experimental Immunology

102

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SUMMARYToxoplasma gondii is able to invade phagocytic cells of the monocyte-macrophage lineage and replicates within a parasitophorous vacuole. Since macrophages may activate specific T lymphocytes by presenting pathogen-derived antigens in association with molecules of the MHC, we investigated the in vitro expression of host cell molecules involved in antigen processing and presentation before and during infection of murine bone marrow-derived macrophages (BMM) with T. gondii. Fifty-one hours after addition of T. gondii tachyzoites at different parasite-to-host ratios, up-regulation of total MHC class II molecules by interferon-gamma (IFN-g) was dose-dependently abrogated in up to 50% of macrophages compared with uninfected control cultures. Quantitative analyses by flow cytometry revealed that the IFN-g-induced surface expression of class II antigens as well as the IFN-g-induced upregulation of class I molecules was significantly decreased in T. gondii-infected macrophage cultures compared with uninfected controls. However, the constitutive expression of MHC class I antigens was not altered after parasitic infection, and infected BMM remained clearly positive for these molecules. After infection of macrophages preactivated with IFN-g for 48 h, T. gondii also actively down-regulated an already established expression of MHC class II molecules. Furthermore, kinetic analysis revealed that the reduction in intracellular and plasma membrane-bound class II molecules started Ϸ 20 h after infection. While MHC class II antigens were most prominently reduced in parasite-positive host cells, culture supernatant from T. gondii-infected BMM cultures also significantly inhibited expression of these molecules in uninfected macrophages. However, down-regulation of MHC class II molecules was not mediated by an increased production of prostaglandin E 2 , IL-10, transforming growth factor-beta or nitric oxide by infected BMM compared with uninfected controls. Our data indicate that intracellular T. gondii interferes with the MHC class I and class II antigen presentation pathway of murine macrophages and this may be an important strategy for evasion from the host's immune response and for intracellular survival of the parasite.

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Cytomegalovirus selectively blocks antigen processing and presentation of its immediate–early gene product

Cited by 248 publications

References 26 publications

Human Cytomegalovirus Proteins pp65 and Immediate Early Protein 1 Are Common Targets for CD8+ T Cell Responses in Children with Congenital or Postnatal Human Cytomegalovirus Infection

Human Cytomegalovirus Proteins pp65 and Immediate Early Protein 1 Are Common Targets for CD8+ T Cell Responses in Children with Congenital or Postnatal Human Cytomegalovirus Infection

Intracellular Retention of the MHC Class I-Related Chain B Ligand of NKG2D by the Human Cytomegalovirus UL16 Glycoprotein

Down-regulation of MHC class II molecules and inability to up-regulate class I molecules in murine macrophages after infection withToxoplasma gondii

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