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

Abstract

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 ...

Circulating Dendritic Cells Isolated from Healthy Seropositive Donors Are Sites of Human Cytomegalovirus Reactivation In Vivo

“…Indirect immunofluorescence for IE72/86 expression, 24 h postinfection (hpi), showed that directly isolated DCs supported HCMV lytic gene expression ( Fig. 2A), consistent with a previous analysis of circulating DCs (38). Furthermore, we observed that the infection was not limited to IE protein expression, since the expression of the structural tegument protein, pp28, was clearly evident by 5 days postinfection (Fig.…”

“…However, crucially, while a wealth of in vitro data supports this prevailing hypothesis, it has never been definitively shown that naturally occurring DCs derived from healthy seropositive individuals are sites of genome carriage and, importantly, sites of HCMV reactivation. Indeed, a previous study of CD11c ϩ dendritic cells isolated from buffy coats of healthy volunteers has suggested that the welldocumented immunoparalysis observed following infection of in vitro-differentiated DCs (20,(30)(31)(32)(33)(34)(35)(36)(37) is not observed when circulating DCs are similarly infected in vitro with HCMV (38). Although these data concern lytic infection, they exemplify the need for a direct analysis of HCMV latency and reactivation in DCs.…”

Human Cytomegalovirus Differentially Controls B Cell and T Cell Responses through Effects on Plasmacytoid Dendritic Cells

“…As in previous reports (15,39), these viruses infected MDCs with high efficiency and PDCs with low efficiency; only 1-12% of PDCs were IE-positive at day 1 p.i. Although late viral RNA was detected in HCMV-infected PDC cultures, the infection appeared to be mainly nonpermissive because no late viral Ags were detected.…”

“…Viral infection leads to maturation of PDCs in an autocrine manner by induced cytokine production, particularly type I IFN and TNF-␣ (27)(28)(29)(30)(31), and HCMV stimulates IFN-␣ and IL-6 secretion in PDCs after 24 -84 h of infection (39,40). We found that PDCs began secreting IFN-␣, TNF-␣, IL-6, and IL-10 within 24 h after exposure to HCMV, regardless of whether they supported viral replication.…”

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

“…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). Although many hints point to an important role for cross-presentation in the priming of the CMV-specific T cell response, experimental research on the contribution of cross-presentation versus direct presentation is still in an early stage.…”