Human cytomegalovirus and immunopathology

Sissons, J. G. P.; Carmichael, Andrew; McKinney, Nicola; Sinclair, John; Wills, Mark R.

doi:10.1007/s00281-002-0104-0

Cited by 35 publications

(29 citation statements)

References 77 publications

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“…CMVs are highly adapted to their hosts. 1 Therefore, it may be difficult to compare results obtained with human cells and animal models. Another possibility is that moDCs are not representative of the DCs that combat HCMV in humans.…”

Section: Introductionmentioning

confidence: 99%

“…1 Thus, the ability to activate cytotoxic T cells is fundamental for a successful immune response. Here we show that CD11c ϩ DCs retain their full capacity to stimulate the proliferation of allogeneic CD4 ϩ and CD8 ϩ T cells on HCMV exposure.…”

Section: Org Frommentioning

confidence: 99%

“…Most primary infections induce minimal symptoms, and there is no clear evidence for clinically relevant immunosuppression. 1 Reactivation of the latent virus is believed to happen frequently, 9,10 but it proceeds asymptomatically in a healthy host, indicating a successful immune response. Indeed, an impressively large part of the T-cell repertoire is HCMV specific in seropositive persons.…”

Section: Introductionmentioning

confidence: 99%

“…Prevalence of HCMV seropositivity ranges between 50% and 90% in healthy adults; after primary infection, the virus establishes lifelong latency in the host. 1 Usually, CMV in immunocompromised patients is caused by the reactivation of latent virus. A number of studies have suggested that the virus may aggravate immunodeficiency by interfering with antigen presentation.…”

mentioning

confidence: 99%

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CD11c+ dendritic cells and plasmacytoid DCs are activated by human cytomegalovirus and retain efficient T cell-stimulatory capability upon infection

Kvale

Dalgaard

Lund-Johansen

et al. 2006

Blood

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IntroductionHuman cytomegalovirus (HCMV) infection represents a major clinical problem in immunocompromised persons, including transplant recipients and AIDS patients. Prevalence of HCMV seropositivity ranges between 50% and 90% in healthy adults; after primary infection, the virus establishes lifelong latency in the host. 1 Usually, CMV in immunocompromised patients is caused by the reactivation of latent virus. A number of studies have suggested that the virus may aggravate immunodeficiency by interfering with antigen presentation. [2][3][4][5][6][7] In these publications, dendritic cells (DCs) have been generated from monocytes or CD34 ϩ bone marrow progenitor cells after 5 to 12 days of cytokine-supplemented culture. Such monocyte-derived DCs (moDCs) or bone marrowderived Langerhans cells are highly potent stimulators of T-cell activation. Exposure of these DCs to HCMV leads to functional paralysis of the cells, causing impaired T-cell activation. [2][3][4][5][6][7] Several mechanisms for this immunosuppression have been suggested. First, major histocompatibility complex (MHC) class I and class II and costimulatory molecules are down-regulated, resulting in impaired antigen presentation and increased susceptibility to natural killer cell-mediated lysis. [2][3][4][5][6][7][8] Second, a virally induced, soluble immunosuppressive factor released by mature moDCs has been postulated by several groups and was recently identified as CD83. 5,7 Third, infection of immature moDCs is lytic and leads to cell death. 7 Studies of HCMV effects on moDCs and Langerhans cells have shed light on mechanisms for viral immune evasion. However, the results showing paralysis of antigen presentation also raise questions as to how HCMV can be so effectively controlled in the immunocompetent host. Most primary infections induce minimal symptoms, and there is no clear evidence for clinically relevant immunosuppression. 1 Reactivation of the latent virus is believed to happen frequently, 9,10 but it proceeds asymptomatically in a healthy host, indicating a successful immune response. Indeed, an impressively large part of the T-cell repertoire is HCMV specific in seropositive persons. Labeling with MHC class I tetramers in complex with HCMV peptides has shown that 1% to 4% of all CD8 ϩ T cells are specific for HCMV proteins. 11,12 In view of the low pathogenicity of HCMV in immunocompetent persons, paralysis of key antigen-presenting cells by the virus seems unlikely.Elegant studies in mice have elucidated mechanisms for successful immunity to murine CMV (MCMV). 13 After injection of virus into mice, a small subset of DCs, termed plasmacytoid dendritic cells (PDCs), produce high levels of IFN-␣, IL-12, and TNF-␣. The rapid innate response is followed by maturation of several welldefined DC subsets in the mouse spleen and initiation of a strong MCMV-directed T-cell response. Frequencies of infected DCs were generally low and were restricted to a subset expressing CD8␣. These results show a high degree of specialization between murine DCs ...

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Section: Introductionmentioning

confidence: 99%

Section: Org Frommentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

CD11c+ dendritic cells and plasmacytoid DCs are activated by human cytomegalovirus and retain efficient T cell-stimulatory capability upon infection

Kvale

Dalgaard

Lund-Johansen

et al. 2006

Blood

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“…family, pathogenic in immunosuppressed or immunodeficient hosts (1), may lie dormant for many years but can cause considerable morbidity and mortality with neonatal or HIV infection or during organ transplantation (2). The large size of the CMV dsDNA genomes (as large as 250 kb), allows these viruses to dedicate many genes to viral fitness; a number of these genes thwart the host inflammatory, innate, and adaptive immune responses.…”

mentioning

confidence: 99%

Structural basis of mouse cytomegalovirus m152/gp40 interaction with RAE1γ reveals a paradigm for MHC/MHC interaction in immune evasion

Wang¹,

Natarajan²,

Revilleza³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Natural killer (NK) cells are activated by engagement of the NKG2D receptor with ligands on target cells stressed by infection or tumorigenesis. Several human and rodent cytomegalovirus (CMV) immunoevasins down-regulate surface expression of NKG2D ligands. The mouse CMV MHC class I (MHC-I)-like m152/gp40 glycoprotein down-regulates retinoic acid early inducible-1 (RAE1) NKG2D ligands as well as host MHC-I. Here we describe the crystal structure of an m152/RAE1γ complex and confirm the intermolecular contacts by mutagenesis. m152 interacts in a pincer-like manner with two sites on the α1 and α2 helices of RAE1 reminiscent of the NKG2D interaction with RAE1. This structure of an MHC-I-like immunoevasin/MHC-I-like ligand complex explains the binding specificity of m152 for RAE1 and allows modeling of the interaction of m152 with classical MHC-I and of related viral immunoevasins.immune recognition | virus evasion | X-ray diffraction C ytomegaloviruses (CMV), members of the β-herpesvirus family, pathogenic in immunosuppressed or immunodeficient hosts (1), may lie dormant for many years but can cause considerable morbidity and mortality with neonatal or HIV infection or during organ transplantation (2). The large size of the CMV dsDNA genomes (as large as 250 kb), allows these viruses to dedicate many genes to viral fitness; a number of these genes thwart the host inflammatory, innate, and adaptive immune responses. Human and mouse studies emphasize the importance of natural killer (NK) and CD8 + T cells in the antiviral response, underscoring the complementary roles of innate and adaptive immunity. Of particular importance to NK-mediated immunity is NKG2D, a C-type lectin-like homodimeric glycoprotein that mediates NK cell activation on ligation by host molecules expressed at the cell surface as a result of cellular or genotoxic stress (3, 4). Human NKG2D ligands include MICA, MICB, and members of the ULBP family (4, 5), and studies suggest a complex relationship between the expression of NKG2D ligands on tumor cells, the effectiveness of immunosurveillance, and clinical prognosis (6, 7). Murine NKG2D recognizes RAE1 family members (RAE1α-ε), H60 (H60a-c), and the murine UL16-binding protein-like transcript 1 (MULT1) (8-10). Remarkably, these NKG2D ligands are related to MHC class I (MHC-I)-like molecules (11,12), and several are targets of MHC-I-like immunoevasins (3). In particular, mouse CMV (MCMV) m152/gp40 (hereafter referred to as "m152") has a dual role, downregulating cell-surface expression of RAE1 family members [but not MULT1 or H60 (13), the targets of MCMV proteins m145 and m155, respectively (14, 15)] as well as host MHC-I molecules (16)(17)(18)(19). A virus-encoded Fc receptor, m138, also controls MULT1, H60 (3), and RAE1ε (20). In vivo, MCMV deletions lacking m145, m152, m155, or m138 are defective in viral control of surface expression of MULT1, RAE1, and H60.To explore the mechanism by which MCMV MHC-I-like immunoevasins interact with and down-regulate their respective NKG2D ligands, we examined th...

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Ex vivo expansion of human cytomegalovirus‐specific cytotoxic T cells by recombinant polyepitope: implications for HCMV immunotherapy

et al. 2005

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Stem cell transplantation (SCT) remains the most effective curative therapy for the majority of hematopoietic malignancies. Unfortunately, SCT is limited by its toxicity and infectious complications that result from profound immunosuppression. In particular, acquisition of exogenous or reactivation of endogenous human cytomegalovirus (HCMV) is common after SCT. More recently, reconstitution of host immunity through augmentation of anti-HCMV T cell responses has been proposed as an exciting candidate therapy to avoid the requirement for antiviral drug use. Here we have developed a novel antigen presentation system based on a replication-deficient adenovirus that encodes multiple HLA class I-restricted epitopes from eight different antigens of HCMV as a polyepitope (referred to as AdCMVpoly). Ex vivo stimulation of peripheral blood mononuclear cells with AdCMVpoly consistently showed rapid stimulation and expansion of multiple epitope-specific T cells that recognized endogenously processed epitopes presented on virus-infected cells. Interestingly, the AdCMVpoly expression system is capable of expanding antigen-specific T cells even in the absence of CD4 + T cells. These studies show the effectiveness of a polyepitope antigen presentation system for reproducible expansion of antigen-specific T cells from immunocompetent and immunocompromised settings.

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Human cytomegalovirus and immunopathology

Cited by 35 publications

References 77 publications

CD11c+ dendritic cells and plasmacytoid DCs are activated by human cytomegalovirus and retain efficient T cell-stimulatory capability upon infection

CD11c+ dendritic cells and plasmacytoid DCs are activated by human cytomegalovirus and retain efficient T cell-stimulatory capability upon infection

Structural basis of mouse cytomegalovirus m152/gp40 interaction with RAE1γ reveals a paradigm for MHC/MHC interaction in immune evasion

Ex vivo expansion of human cytomegalovirus‐specific cytotoxic T cells by recombinant polyepitope: implications for HCMV immunotherapy

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