CD8 T Cell–Evasive Functions of Human Cytomegalovirus Display Pervasive MHC Allele Specificity, Complementarity, and Cooperativity

Ameres, Stefanie; Besold, Katrin; Plachter, Bodo; Moosmann, Andreas

doi:10.4049/jimmunol.1302281

Cited by 29 publications

(28 citation statements)

References 76 publications

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“…To circumvent this problem, we chose an HCMV strain that lacked several of the MHC immunoevasins. Such strains modulate antigen presentation to a lesser extent than HCMV isolates expressing the full complement of immunoevasins [73, 74]. In view of these considerations, we value the comparable activation and proliferation of HCMV-specific T cells observed upon co-cultivation with ULBP2-TB40 and TB40 infected DCs (Figs 3 and 4C) as a positive result.…”

Section: Discussionmentioning

confidence: 86%

Activation of Innate and Adaptive Immunity by a Recombinant Human Cytomegalovirus Strain Expressing an NKG2D Ligand

et al. 2016

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Development of an effective vaccine against human cytomegalovirus (HCMV) is a need of utmost medical importance. Generally, it is believed that a live attenuated vaccine would best provide protective immunity against this tenacious pathogen. Here, we propose a strategy for an HCMV vaccine that aims at the simultaneous activation of innate and adaptive immune responses. An HCMV strain expressing the host ligand ULBP2 for the NKG2D receptor was found to be susceptible to control by natural killer (NK) cells, and preserved the ability to stimulate HCMV-specific T cells. Infection with the ULBP2-expressing HCMV strain caused diminished cell surface levels of MHC class I molecules. While expression of the NKG2D ligand increased the cytolytic activity of NK cells, NKG2D engagement in CD8+ T cells provided co-stimulation and compensated for lower MHC class I expression. Altogether, our data indicate that triggering of both arms of the immune system is a promising approach applicable to the generation of a live attenuated HCMV vaccine.

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Section: Discussionmentioning

confidence: 86%

Activation of Innate and Adaptive Immunity by a Recombinant Human Cytomegalovirus Strain Expressing an NKG2D Ligand

et al. 2016

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“…32–34 More recent studies also indicate that presentation of CMVpp65 peptides, which does not require new protein synthesis, may be less susceptible to inhibition by subsequently generated evasins, the non-coding RNAs generated by CMV that can interfere with antigen processing and TAP mediated transport of antigen peptides to HLA alleles for presentation. 35,36 …”

Section: Discussionmentioning

confidence: 99%

“…For example, evasins such as US2,3,6 and 11 can disrupt the membrane localization and stability of specific MHC class I alleles, thereby impairing their expression. 35,49,50 US3 and US6 can also prevent the transport and loading of processed peptides on HLA class I alleles for presentation to T-cells. 36 In addition, Kim et al 51 have recently shown that a CMV micro RNA US4-1 can downregulate the expression of an aminopeptidase essential to the editing of antigenic peptides during their processing within the endoplasmic reticulum.…”

Section: Discussionmentioning

confidence: 99%

Immunotherapy with Donor T Cells Sensitized with Overlapping Pentadecapeptides for Treatment of Persistent Cytomegalovirus Infection or Viremia

Koehne

Hasan

Doubrovina

et al. 2015

Biology of Blood and Marrow Transplantation

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We conducted a Phase I trial of allogeneic T-cells sensitized in vitro against a pool of 15-mer peptides spanning the sequence of CMVpp65 for adoptive therapy of 17 allogeneic hematopoietic cell transplant recipients with CMV viremia or clinical infection persisting despite prolonged treatment with antiviral drugs. All but three of the patients had received T-cell depleted transplants without GVHD prophylaxis with immunosuppressive drugs post transplant. The CMVpp65-specific T-cells (CMVpp65CTLs) generated were oligoclonal and specific for only 1–3 epitopes, presented by a limited set of HLA class I or II alleles. T-cell infusions were well tolerated without toxicity or GVHD. Of 17 patients treated with transplant donor (N=16) or third party (N=1) CMVpp65CTLs, 15 cleared viremia including 3 of 5 with overt disease. In responding patients, the CMVpp65CTLs infused consistently proliferated and could be detected by T-cell receptor (TCR) Vβ usage in CMVpp65/HLA tetramer+ populations for period of 120 days to up to 2 years post infusion. Thus, CMVpp65CTLs generated in response to synthetic 15-mer peptides of CMVpp65 are safe and can clear persistent CMV infections in the post transplant period.

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“…We want to point out that both mutants also lacked ORFs US2 to US6 encoding immune evasins and were therefore expected to modulate HLA expression to a lesser extent than wildtype CMV (61). This characteristic of the mutants appeared to be a prerequisite for measuring the influence of UL11 on T cell activity, because many CMV-specific T cells are hardly activated when HLA levels are diminished (62,63). Immunoblot analysis of cells infected with the two mutants confirmed the similar expression of the IE1 and pp65 proteins (Fig.…”

Section: Expression Of Ul11 Proteins During the Lytic CMV Infection Cmentioning

confidence: 99%

Expression of the Human Cytomegalovirus UL11 Glycoprotein in Viral Infection and Evaluation of Its Effect on Virus-Specific CD8 T Cells

Gabaev

Elbasani

Ameres

et al. 2014

J Virol

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The human cytomegalovirus (CMV) UL11 open reading frame (ORF) encodes a putative type I transmembrane glycoprotein which displays remarkable amino acid sequence variability among different CMV isolates, suggesting that it represents an important virulence factor. In a previous study, we have shown that UL11 can interact with the cellular receptor tyrosine phosphatase CD45, which has a central role for signal transduction in T cells, and treatment of T cells with large amounts of a soluble UL11 protein inhibited their proliferation. In order to analyze UL11 expression in CMV-infected cells, we constructed CMV recombinants whose genomes either encode tagged UL11 versions or carry a stop mutation in the UL11 ORF. Moreover, we examined whether UL11 affects the function of virus-specific cytotoxic T lymphocytes (CTLs). We found that the UL11 ORF gives rise to several proteins due to both posttranslational modification and alternative translation initiation sites. Biotin labeling of surface proteins on infected cells indicated that only highly glycosylated UL11 forms are present at the plasma membrane, whereas less glycosylated UL11 forms were found in the endoplasmic reticulum. We did not find evidence of UL11 cleavage or secretion of a soluble UL11 version. Cocultivation of CTLs recognizing different CMV epitopes with fibroblasts infected with a UL11 deletion mutant or the parental strain revealed that under the conditions applied UL11 did not influence the activation of CMV-specific CD8 T cells. For further studies, we propose to investigate the interaction of UL11 with CD45 and the functional consequences in other immune cells expressing CD45. IMPORTANCEHuman cytomegalovirus (CMV) belongs to those viruses that extensively interfere with the host immune response, yet the precise function of many putative immunomodulatory CMV proteins remains elusive. Previously, we have shown that the CMV UL11 protein interacts with the leukocyte common antigen CD45, a cellular receptor tyrosine phosphatase with a central role for signal transduction in T cells. Here, we examined the proteins expressed by the UL11 gene in CMV-infected cells and found that at least one form of UL11 is present at the cell surface, enabling it to interact with CD45 on immune cells. Surprisingly, CMVexpressed UL11 did not affect the activity of virus-specific CD8 T cells. This finding warrants investigation of the impact of UL11 on CD45 functions in other leukocyte subpopulations.

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CD8 T Cell–Evasive Functions of Human Cytomegalovirus Display Pervasive MHC Allele Specificity, Complementarity, and Cooperativity

Cited by 29 publications

References 76 publications

Activation of Innate and Adaptive Immunity by a Recombinant Human Cytomegalovirus Strain Expressing an NKG2D Ligand

Activation of Innate and Adaptive Immunity by a Recombinant Human Cytomegalovirus Strain Expressing an NKG2D Ligand

Immunotherapy with Donor T Cells Sensitized with Overlapping Pentadecapeptides for Treatment of Persistent Cytomegalovirus Infection or Viremia

Expression of the Human Cytomegalovirus UL11 Glycoprotein in Viral Infection and Evaluation of Its Effect on Virus-Specific CD8 T Cells

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