Human cytomegalovirus induces a direct inhibitory effect on antigen presentation by monocyte‐derived immature dendritic cells

Grigoleit, Ulrich; Riegler, Susanne; Einsele, Hermann; Sampaio, Kerstin Laib; Jahn, Gerhard; Hebart, Holger; Brossart, Peter; Frank, Friderike; Sinzger, Christian

doi:10.1046/j.1365-2141.2002.03798.x

Cited by 59 publications

(77 citation statements)

References 29 publications

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“…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.…”

Section: Introductionmentioning

confidence: 99%

“…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.…”

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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%

mentioning

confidence: 99%

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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“…On the contrary, there are results that indicated some leakiness in the functions of vRAPs (40)(41)(42). However, even if infected DCs retain a residual capacity for Ag presentation, a series of additional viral mechanisms ranging from downregulation of costimulatory molecules over changes in the secretion of chemokines and cytokines to the inhibition of migration and maturation may severely impair DC functions (17,18,(43)(44)(45)(46)(47)(48)(49)(50)). Yet again, there are studies that report on host countermeasures that retain the function of DCs after CMV infection (51)(52)(53).…”

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confidence: 99%

Priming of CD8+ T Cells against Cytomegalovirus-Encoded Antigens Is Dominated by Cross-Presentation

Busche

Jirmo

Welten

et al. 2013

The Journal of Immunology

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CMV can infect dendritic cells (DCs), and direct Ag presentation could, therefore, lead to the priming of CMV-specific CD8+ T cells. However, CMV-encoded immune evasins severely impair Ag presentation in the MHC class I pathway; thus, it is widely assumed that cross-presentation drives the priming of antiviral T cells. We assessed the contribution of direct versus cross priming in mouse CMV (MCMV) infection using recombinant viruses. DCs infected with an MCMV strain encoding the gB498 epitope from HSV-1 were unable to stimulate in vitro naive gB498-specific CD8+ T cells from TCR transgenic mice. Infection of C57BL/6 mice with this recombinant virus led, however, to the generation of abundant numbers of gB498-specific T cells in vivo. Of the DC subsets isolated from infected mice, only CD8α+ DCs were able to stimulate naive T cells, suggesting that this DC subset cross-presents MCMV-encoded Ag in vivo. Upon infection of mice with MCMV mutants encoding Ag that can either be well or hardly cross-presented, mainly CD8+ T cells specific for cross-presented epitopes were generated. Moreover, even in the absence of immune evasion genes interfering with MHC class I–mediated Ag presentation, priming of T cells to Ag that can only be presented directly was not observed. We conclude that the host uses mainly DCs capable of cross-presentation to induce the CMV-specific CD8+ T cell response during primary, acute infection and discuss the implications for the development of a CMV vaccine.

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“…They may distribute virus from peripheral entry sites towards lymphatic tissue; and infection of DC may pivotally result either in immunosuppression or in immune activation, depending on the cytopathic effect (CPE) of the virus. DCs are among the first cells encountered by viruses, and can be infected by viruses such as LCMV (23), Lassa fever virus (24,25), human cytomegalovirus (26)(27)(28), Influenza virus (29), and Measles virus (30,31). Many of them can finish complete life cycles in DCs and also produce an infectious virus.…”

Section: Discussionmentioning

confidence: 99%

Human membrane protein Tim-3 facilitates hepatitis A virus entry into target cells

Sui

Li²,

Zhang³

et al. 2006

Int J Mol Med

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Abstract. In this study, a cellular surface membrane protein of immunoglobulin (Ig) superfamily (IgSF) was identified from a human dendritic cell (DC) cDNA library by largescale random sequencing, which is identical to previously reported Tim-3 (T-cell Ig-and mucin-domain-containing molecule 3). Recent data have suggested the association of the 281-residue mouse Tim-3 molecule with Th1-related T cell responses and disease in mice. Human Tim-3 is a 301-residue type I membrane protein whose extracellular region contains a Cys-rich Ig-like domain and a mucin domain, the characteristics of Tim proteins. It shows significant homology to human hepatitis A virus (HAV) cellular receptor-1 (HuHAVcr-1)/Tim-1. Human Tim-3 mRNA was highly expressed in monocytes or monocyte-derived cells, and the expression level decreased when DC underwent maturation and activation. There is no previous report on the biological functions of human Tim-3, especially the involvement in virus infection. We demonstrated that HeLa cells, which are refractory to HAV infection, acquired a limited susceptibility to HAV infection after stably overexpressing human Tim-3 as confirmed by Western blot analysis using anti-Tim-3 antibody, but Tim-3-Fc fusion protein had no direct HAV-binding activity. The results indicated that human Tim-3 can promote HAV entry into target cells but itself may not function as a cellular receptor of HAV. IntroductionHAV (hepatitis A virus), the causative agent of hepatitis in human, produces substantial morbidity and mortality, with an estimated 125,000-200,000 infections occurring each year (1). HAV is an atypical member of the Picornaviridae, and is the only member of the hepatovirus genus of the Picornaviridae, a family of small, nonenveloped, positive-strand RNA viruses that include human pathogens such as poliovirus (PV) and rhinovirus as well as animal pathogen such as foot-and-mouth disease virus and encephalomyocarditis virus (2). Most wildtype strains of HAV do not grow in cell culture; however, attenuated variants that grow efficiently in primate cell culture have been isolated on serial passaging of the virus (3-5). HAV has also been adapted to grow in guinea pig, pig, and dolphin cell culture, indicating that the cellular factors required for HAV replication are not restricted to primates (6,7). Like other picornaviruses, the first step in the life cycle of HAV is its interaction with a cellular receptor that allows it to enter the cells. Using the protective monoclonal antibody 190/4 as a probe, Kaplan et al identified the HAV cellular receptor-1 (HAVcr-1) in African green monkey cells as a receptor of HAV (8,9). Later, the same research group proved the existence of human homologue of HAVcr-1. It was named HuHAVcr-1, which is the first identified attachment and cellular receptor of HAV in humans. HuHAVcr-1 encodes a polypeptide of 359 amino acids, with typical features of type I integral-membrane glycoprotein (10). The extracellular domain of HuHAVcr-1 contains an N-terminal cysteine-rich region, which shares ...

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Human cytomegalovirus induces a direct inhibitory effect on antigen presentation by monocyte‐derived immature dendritic cells

Cited by 59 publications

References 29 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

Priming of CD8+ T Cells against Cytomegalovirus-Encoded Antigens Is Dominated by Cross-Presentation

Human membrane protein Tim-3 facilitates hepatitis A virus entry into target cells

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