Human cytomegalovirus inhibits maturation and impairs function of monocyte-derived dendritic cells

Abstract

Whereas virus infections in general stimulate DC maturation and lead to the generation of efficient antiviral T-cell responses, some viruses have developed mechanisms to interfere with the normal functions of DCs. Human immunodeficiency virus (HIV), measles virus, herpes simplex virus-1 (HSV-1), and vaccinia virus, for example, are all known to cause defects in DC maturation and function which consequently lead to impaired antiviral T-cell responses. [1][2][3][4] The major risk factor for HCMV infection in bone marrow transplant patients is their pre-existing seropositive status. 5 Delayed reconstitution of the antiviral cellular immune response in these patients is often associated with HCMV infection and progressive disease with poor prognosis. CD8 ϩ T cells are the main cell type controlling HCMV infection as proven by their successful adoptive transfer preventing viraemia and HCMV disease in bone marrow transplant recipients. 6 HCMV infection is also associated with serious secondary bacterial or fungal infections in immunosuppressed patients, 7,8 although during the early phase of acute HCMV infection, transiently suppressed cellular immune responses 9,10 and immunologic abnormalities of healthy individuals 11 were also reported. HCMV has been shown to interfere with antigen presentation in fibroblasts and endothelial cells 12 by (1) expressing viral proteins which interfere with the MHC class I antigenpresenting pathways (US3, US2, US11); (2) modulating antigen procession of the HCMV immediate early 1 (IE1) protein (pp65); and (3) preventing peptide transport through TAP proteins (US6). However, little is known about whether the induction phase of HCMV-specific T-cell responses is also affected. From the few studies that looked at HCMV infection of monocytes, macrophages, and DCs, [13][14][15] only one seemed to establish a link between HCMV infection of macrophages and impaired proliferation of CD4 ϩ T cells upon stimulation with these macrophages. 15 We hypothesized that similar to its effects in fibroblasts and endothelial cells, HCMV also inhibits the expression of MHC class I molecules in DCs. Although this inhibitory effect alone would probably be sufficient to prevent or impair the generation of virus-specific primary T-cell responses, other important features such as the expression of costimulatory molecules, the production of proinflammatory cytokines, and the antigen-presenting function of monocyte-derived DCs were also studied following HCMV infection. We show that HCMV impairs all these properties of DCs. The viral inhibition may contribute not only to the successful establishment of latency by HCMV but also to the immunosuppression observed in association with the infection. Patients, materials, and methods DonorsHCMV seropositive and seronegative healthy laboratory volunteers were included in this study. Ethical approval was obtained and informed consent Cell lines and tissue culture reagentsHuman foreskin fibroblasts (HFFs) were cultured in minimum essential medium (MEM; Sigma, St Louis, MO...

Simultaneous quantification of human cytomegalovirus (HCMV)-specific CD4+ and CD8+T cells by a novel method using monocyte-derived HCMV-infected immature dendritic cells

“…It was previously reported that clinical HCMV isolates (in contrast to laboratory strains and HELF-adapted clinical isolates) are able to infect DC [21]. HCMV infection has been reported to inhibit DC maturation as shown by down-regulation of surface MHC and costimulatory molecule expression [22]. In our study, we found that two molecules highly expressed in the mature pheno- type (MHC class I and CD40) were partially downregulated in HCMV-infected DC, and HLA-DR was only partially up-regulated, while CD83 was not expressed.…”

Persistent and Selective Deficiency of CD4+ T Cell Immunity to Cytomegalovirus in Immunocompetent Young Children

“…These include the US2 and US3, which have been shown to directly interfere with class II MHC Ag presentation (46,47), and a viral orthologue of IL-10 that has similar immunosuppressive properties as human 45). CMV can also directly infect human myeloid dendritic cells (48,49), which are key APCs for the initiation of the adaptive immune response and in directing CD4 ϩ T cell differentiation toward Th1 effector function or other fates (50). Such infection may interfere with the ability of dendritic cells to present Ags to CD4 ϩ T cells (48) and produce IL-12 (49), a key cytokine for the generation of Th1 cells in humans (25).…”

The immunology of human cytomegalovirus latency: could latent infection be cleared by novel immunotherapeutic strategies?

“…22 In addition, the virus also encodes proteins that act as receptors for host inflammatory cytokines, thereby reducing localized cytokine effectiveness by acting as cytokine sinks. 6 Similarly, a number of HCMV encoded genes known to be expressed during lytic infection can interfere with both MHC Class I and II restricted antigen processing and presentation, thereby robustly inhibiting CD4 1 and CD8 1 T-cell recognition 4,23 as well as costimulatory T-cell signalling 24 (Figure 3). On the one hand then, HCMV expresses multiple immunevasins which are known to work potently in vitro but, even in the face of these, host immune response are still able to resolve primary HCMV infection.…”