Phenotypic and Functional Alterations of Dendritic Cells Induced by Human Herpesvirus 6 Infection

Kakimoto, Miki; Hasegawa, Atsuhiko; Fujita, Shigeru; Yasukawa, Masaki

doi:10.1128/jvi.76.20.10338-10345.2002

Cited by 60 publications

(56 citation statements)

References 57 publications

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“…In marked contrast to herpesviruses such as CMV and EBV, the interaction of HHV-6 and the immune system was interpreted predominantly in terms of the immunosuppressive effects of the virus [16]. Because HHV-6 may inhibit T cells [17,18,36] and APCs [19,37] by a variety of mechanisms, some of them operative only in infected cells but some also in bystander cells, HHV-6 has been described as an immunosuppressive virus [16]. This has left open the question how healthy carriers control HHV-6 infection, and how virus-specific T cells may contribute to control, although such knowledge is essential for an understanding of HHV-6 disease and the development of new (immuno) therapies.…”

Section: Discussionmentioning

confidence: 99%

Specific CD8⁺T cells recognize human herpesvirus 6B

et al. 2012

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The importance of human herpesvirus 6 (HHV-6) species as human pathogens is increasingly appreciated. However, we do not understand how infection is controlled in healthy virus carriers, and why control fails in patients with disease. Other persistent viruses are under continuous surveillance by antigen-specific T cells, and specific T-cell repertoires have been well characterized for some of them. In contrast, knowledge on HHV-6-specific T-cell responses is limited, and missing for CD8 + T cells. Here we identify CD8 + T-cell responses to HHV-6B, the most widespread HHV-6 species, in healthy virus carriers. HHV-6B-specific CD8 + T-cell lines and clones recognized HLA-A2-restricted peptides from the viral structural proteins U54 and U11, and displayed various antigenspecific antiviral effector functions. These CD8 + T cells specifically recognized HHV-6B-infected primary CD4 + T cells in an HLA-restricted manner, produced antiviral cytokines, and killed infected cells, whereas HHV-6A-infected cells were not recognized. Thus, HHV-6B-specific CD8 + T cells are likely to contribute to control of infection, overcoming the immunomodulatory effects exerted by the virus. Potentially, HHV-6-associated disease could be addressed by active or passive immunotherapy that reconstitutes virusspecific CD8 + T-cell responses. Keywords: CD8+ T cells r human herpesvirus 6B r infectious diseases r virology IntroductionHuman herpesvirus 6 (HHV-6) species are widespread pathogens, and more than 90% of humans are seropositive. The two species HHV-6A and HHV-6B have close sequence homology but differ in their epidemiology and pathogenicity [1,2]. Primary infection with HHV-6B, the more widespread species, usually takes place in early childhood and is often associated with a self-limiting illness known as three-day fever or exanthema subitum [3,4]. After primary infection, HHV-6 remains in a latent state in its immunocompetent host [5], and occasional reactivations are normally asymptomatic. However, HHV-6 (in most cases HHV-6B) can reactivate in immunosuppressed individuals. HHV-6B reactivation is observed in 40-50% of patients receiving stem cell transCorrespondence: Dr. Andreas Moosmann e-mail: andreas.moosmann@helmholtz-muenchen.de plantation, and viral reactivation is associated with delirium and cognitive decline, severe encephalitis, graft-versus-host disease, transplant failure, and overall mortality [6][7][8][9]. Apart from the immunosuppressed host, HHV-6 has been involved in a variety of diseases involving the CNS, such as febrile seizures, encephalitis, epilepsy, and multiple sclerosis [2,10]. Healthy humans frequently carry a number of other persistent viruses that may reactivate under immunosuppression, including the herpesvirus family members Epstein-Barr virus (EBV) and cytomegalovirus (CMV) [11]. It is assumed that these viruses are under continuous control by antigen-specific T cells, and viral reactivation results from a deficiency in virus-specific T cells caused by therapy-related immunosuppression [11]. In accorda...

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Section: Discussionmentioning

confidence: 99%

Specific CD8⁺T cells recognize human herpesvirus 6B

et al. 2012

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“…Next, we determined the capacity of infected DCs to stimulate normal T cells in an allogeneic mixed lymphocyte response, a standard functional readout for pathogen-infected DCs (37)(38)(39)(40). As shown in Fig.…”

Section: ␥Hv68 Infection Of Dendritic Cells Inhibits the Proliferatiomentioning

confidence: 99%

Infection of Dendritic Cells by a γ2-Herpesvirus Induces Functional Modulation

Flaño

Kayhan

Woodland

et al. 2005

The Journal of Immunology

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The murine γ-herpesvirus-68 (γHV68) establishes viral latency in dendritic cells (DCs). In the present study, we examined the specific consequences of DC infection by γHV68, both in vivo and in vitro. Ex vivo analysis of infected mice showed that the virus colonizes respiratory DCs very early after infection and that all subsets of splenic DCs analyzed are viral targets. We have developed and characterized an in vitro model of γHV68 infection of DCs. Using this model, we demonstrated that viral infection neither induces full DC maturation nor interferes with exogenous activation, which is assessed by cell surface phenotypic changes. However, whereas γHV68 infection alone failed to elicit cytokine secretion, IL-10 secretion of exogenously activated DCs was enhanced. Furthermore, γHV68-infected DCs efficiently stimulated virus-specific T cell hybridomas but failed to induce alloreactive stimulation of normal T cells. These data indicate that viral infection doesn’t interfere with Ag processing and presentation but does interfere with the ability of DCs to activate T cells. The inhibition of T cell activation was partially reversed by blocking IL-10. Analysis of infected mice shows elevated levels of IL-10 expression in DCs and that lack of endogenous IL-10 is associated with decreased γHV68 long-term latency. Taken together, these observations indicate that γ2-herpesvirus infection of DCs is a mechanism of viral immune evasion, partially mediated by IL-10.

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“…Because of their central role in the induction of immune responses, the modulation of DC maturation and functional activity represents a strategic mechanism for a pathogen to evade immune surveillance. In this regard, growing evidence is accumulating on the capacity of some viruses to differently affect DC biology, ultimately leading to an impairment of antiviral immune responses (8,13,15,18,22,25,27,30,37,38).…”

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confidence: 99%

Human Immunodeficiency Virus Type 1 gp120 Induces Abnormal Maturation and Functional Alterations of Dendritic Cells: a Novel Mechanism for AIDS Pathogenesis

Fantuzzi

Purificato

Donato

et al. 2004

J Virol

101

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Dendritic cells (DCs) play a crucial role in bridging innate and acquired immune responses to pathogens. In human immunodeficiency virus type 1 (HIV-1) infection, immature DCs (iDCs) are also main targets for HIV-1 at the mucosal level. In this study, we evaluated the effects of HIV-1-DC interactions on the maturation and functional activity of these cells. Exposure of human monocyte-derived iDCs to either aldrithiol-2-inactivated HIV-1 or gp120 led to an upmodulation of activation markers indicative of functional maturation. Despite their phenotype, these cells retained antigen uptake capacity and showed an impaired ability to secrete cytokines or chemokines and to induce T-cell proliferation. Although gp120 did not interfere with DC differentiation, the capacity of these cells to produce interleukin-12 (IL-12) upon maturation was markedly reduced. Likewise, iDCs stimulated by classical maturation factors in the presence of gp120 lacked allostimulatory capacity and did not produce IL-12, in spite of their phenotype typical of activated DCs. Exogenous addition of IL-12 restores the allostimulatory capacity of gp120-exposed DCs. The finding that gp120 induces abnormal maturation of DCs linked to profound suppression of their activities unravels a novel mechanism by which HIV can lead to immune dysfunction in AIDS patients.

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Phenotypic and Functional Alterations of Dendritic Cells Induced by Human Herpesvirus 6 Infection

Cited by 60 publications

References 57 publications

Specific CD8⁺T cells recognize human herpesvirus 6B

Specific CD8⁺T cells recognize human herpesvirus 6B

Infection of Dendritic Cells by a γ2-Herpesvirus Induces Functional Modulation

Human Immunodeficiency Virus Type 1 gp120 Induces Abnormal Maturation and Functional Alterations of Dendritic Cells: a Novel Mechanism for AIDS Pathogenesis

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Phenotypic and Functional Alterations of Dendritic Cells Induced by Human Herpesvirus 6 Infection

Cited by 60 publications

References 57 publications

Specific CD8+T cells recognize human herpesvirus 6B

Specific CD8+T cells recognize human herpesvirus 6B

Infection of Dendritic Cells by a γ2-Herpesvirus Induces Functional Modulation

Human Immunodeficiency Virus Type 1 gp120 Induces Abnormal Maturation and Functional Alterations of Dendritic Cells: a Novel Mechanism for AIDS Pathogenesis

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Specific CD8⁺T cells recognize human herpesvirus 6B

Specific CD8⁺T cells recognize human herpesvirus 6B