Scribd Logo
Upload

Welcome to Scribd!

  • 20140527090839962

    Uploaded by

    Joshua Blumberg
    9 views30 pages
    art

    Copyright

    © © All Rights Reserved

    Available Formats

    PDF or read online from Scribd

    Did you find this document useful?

    Is this content inappropriate?

    Report this Document
    art

    Copyright:

    © All Rights Reserved
    Download as PDF or read online from Scribd
    Flag for inappropriate content
    9 views30 pages

    20140527090839962

    Uploaded by

    Joshua Blumberg
    art

    Copyright:

    © All Rights Reserved
    Download as PDF or read online from Scribd
    Flag for inappropriate content
    of 30
    Dendritic cells in cytomegalovirus infection: viral evasion and host countermeasures - RO... Page 1 of 30 | @WILEY ff ONLINE LIBRARY. ADVANCED SEARCH | deuttale Becks Batabanre t tab You have free access to this content Dendritic cells in cytomegalovirus infection: viral evasion and host countermeasures 1, ALEXANDER ROLLE, 2. JOHANNA OLWEUS Article first published online: 21 APR 2009 DOI: 10.1111.1600-0463.2009.02449.x © 2009 The Authors, Journal Compilation © 2009 APMIS Issue APMIS Volume 117, Issue 5-6, pages 413-426, May/June 2009 Additional Information How to Cite ROLLE, A. and OLWEUS, J. (2009), Dendritic cells in cytomegalovirus infection: viral evasion and host countermeasures. APMIS, 117: 413-426. doi: 10.1111/.1600-0463.2009.02449.x. Author Information Department of Immunology, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, University of Oslo, Oslo, Norway *Correspondence: Alexander Rélle, Department of Immunology, Institute for Cancer Research, Radiumhospitalet-Rikshospitalet, Montebello, 0310 Oslo, Norway. e-mail: alexander.rolle@sr- hitp://onlinelibrary.wiley.com/doi/10.1111/}.1600-0463.2009.02449.x/full 12/4/2011 Dendritic cells in cytomegalovirus infection: viral evasion and host countermeasures - RO... Page 2 of 30 research.no Publication History 1, Issue published online: 21 APR 2009 2. Article first published online: 21 APR 2009 3. Invited review Abstract Article References Cited By Get PDF (239K) Keywords: DCs; pDCs; moDCs; HCHV; NK cells Abstract Juman cytomegalovirus (HCMV) is a B-herpesvirus that infects the majority of the population during carly childhood and thereafter establishes life-long latency. Primary infection as well as spontaneous ‘activation usually remains asymptomatic in healthy hosts but can, in the context of systemic mmunosuppression, result in substantial morbidity and mortality. HCMV counteracts the host immune ‘esponse by interfering with the recognition of infected cells. A growing body of literature has also suggested that the virus evades the immune system by paralyzing the initiators of antiviral immune ‘esponses — the dendritic cells (DCs). In the current review, we discuss the effects of CMV (HCMV and nurine CMV) on various DC subsets and the ensuing innate and adaptive immune responses. The mpact of HCMV on DCs has mainly been investigated using monocyte-derived DCs, which are ‘endered functionally impaired by infection. In mouse models, DCs are targets of viral evasion as well, out the complex cross-talk between DCs and natural killer cells has, however, demonstrated an nstrumental role for DCs in the control and clearance of viral infection. Fewer studies address the role of peripheral blood DC subsets, plasmacytoid DCs and CD11¢* myeloid DCs in the response against ICMY. These DCs, rather than being paralyzed by HCMV, are largely resistant to infection, mount a ‘igorous first-line defense and induce T-cell responses to the virus. This possibly provides a partial -xplanation for an intriguing conundrum: the highly efficient control of viral infection and reactivation n immunocompetent hosts in spite of multi-layered viral evasion mechanisms. Juman cytomegalovirus (HCMV) has been the focus of intense research in several disciplines over the ast 15 years, This work yielded not only exciting insights into viral pathogenesis and the ensuing ‘mune response but also made central contributions to cell biology, e.g. the elucidation of the complex cellular antigen processing and presentation machinery. http://onlinelibrary.wiley.com/doi/10.11114.1600-0463.2009.02449.x/fall 12/4/2011 Dendritic cells in cytomegalovirus infection: viral evasion and host countermeasures - RO... Page 3 of 30 Primary HCMY infection occurs early in life, usually by transmission through saliva or breastmilk, leading to a high sero-prevalence of 40-90%, depending on the country. Infection results in the establishment of latency, a state in which the virus resides silently in certain cell types while no or only very few viral genes are transcribed. Like primary infection, episodes of spontaneous reactivation usually remain asymptomatic (1). Under certain circumstances, such as systemic immunosuppression, the virus gives tise to substantial morbidity and mortality. Typical patient groups are AIDS patients or transplant recipients, where CMV disease often manifests itself with retinitis, hepatitis, encephalitis or pneumonitis. HCMV is also the most common viral cause of congenital disorders, resulting in neuronal impairments, growth retardation and jaundice in the fetus, particularly when primary infection occurs in the first trimester of the pregnancy (1). The focus of this review is the complex pathogen-host relationship in CMV infection, with particular emphasis on dendritic cells (DCs) and their role in the initiation and co-ordination of host defenses against the virus. After a brief introduction to the impressive range of immuno-evasive or -modulatory strategies used by CMY, we will discuss the effects of infection on different subsets of DCs and the consequences for subsequent immune responses. Beyond their role in priming of adaptive immunity, DCs are increasingly appreciated for the extensive cross-talk they maintain with other innate immune cells, most notably natural killer (NK) cells. Therefore, in the second part, we will discuss our current view of the interactions taking place between NK cells and DCs and highlight the consequences of CMV infection for this cross-talk, Throughout this review, we will also refer to the model of murine CMV (MCMV), which, in recent years, has allowed many key questions to be addressed and has advanced our understanding of immunity to CMV considerably. IMMUNE EVASION BY HCMV Interference with antigen presentation and processing Antigen presentation, a crucial requirement for successful immune responses, relies on the major xistocompatibility complex (MHC), in humans also termed human leukocyte antigen (HLA). MHC nolecules are expressed on the cell surface and present short peptides to surveilling immune cells. >eptides in the context of MHC class I are predominantly presented to CD8* T cells, whereas MHC lass Il-restricted peptides are recognized mainly by CD4*T cells. n MHC class I molecules, peptides are generated primarily by proteasomal degradation of cytosolic yroteins and consecutively transported into the endoplasmic reticulum (ER) by the transporter associated vith antigen processing (TAP). MHC class II molecules are instead loaded in lysosomes, where they \ssociate with peptides derived from endocytosed exogenous proteins or endogenous proteins that enter he lysosomal compartment (2). In DCs, exogenous proteins can eventually gain access to MHC class I http://onlinelibrary.wiley.com/doi/10.1111/.1600-0463.2009.02449.x/full 12/4/2011 Dendritic cells in cytomegalovirus infection: viral evasion and host countermeasures - RO... Page 4 of 30 ‘as well —a phenomenon termed cross-presentation (3). This pathway permits antigens that are normally loaded onto MHC class IT molecules to enter the MHC class I presentation pathway. Cross-presentation allows DCs to present viral antigens to CD8 ' T cells without being infected themselves. ae =e As a member of the B-herpesvirus family, HCMV harbors a large double-stranded DNA genome, encoding for dozens of genes devoted to pathogen-host interactions and immune evasion. More than 50 ORFs are dispensable for viral growth in vitro and as such potentially involved in immune modulation. Given that ultimately the control of HCMV and other herpesvirus infections is achieved by CD8* T cells (4-6), itis perhaps not surprising that a substantial part of those genes are devoted to counteracting or limiting the T-cell recognition of infected cells by interfering with the MHC class I and II antigen presentation pathways. This interference leads to decreased surface levels of MHC molecules on infected cells (a strategy that isnot limited to herpesviruses, as itis also used by other virus families, such as adeno- or lentiviruses) (7). In HCMY, to date, six different viral genes have been described to interfere with MHC class I (and II) pathways. The tegument protein pp65 prevents processing of the viral immediate early antigen-1 (IE-1) for presentation (8). The US2 and USI1 genes downregulate MHC class I molecules by rapidly translocating them to the eytosol, where they become tagged for proteasomal degradation (9, 10). US2 and US1I differ in terms of allele specificity and the maturation stage in which they bind to MHC class I within the ER (11). Other targets of US2 have been identified as MHC class If proteins and the non-classical MHC class I molecule HIFE, respectively (12.13). ‘Additional immuno-evasive genes include US3, which retains MHC class I molecules and interferes with MAC class If (14,15), and US6, which blocks TAP funetion (16), thereby preventing the loading of MHC class I molecules with peptides (17), a mode of action that resembles the HSV-1 protein ICP47 (18). Less well studied is US10, which is possibly involved in delaying intracellular MHC class I trafficking (19). UL82, encoding pp71, has recently been suggested to possess additional functions besides its known role in viral replication, namely to inhibit the transport of MHC class I between ER and cis-Golgi (20). Other immune evasins described for HCMY comprise a viral IL-10 homolog (21), chemokine (receptor) homologs (22,23) and viral gene products regulating cell-cycle progression or inhibiting apoptosis (24-26). Interference with DC function Subversion of MHC class I and II pathways appears to be a logical strategy from the perspective of HCMV, because it directly interferes with T-cell activation. While these mechanisms are operational in all infected cells expressing MHC class I and Il, a growing body of literature describes a more specific impairment of DC functions by HCMV that could further compromise the mounting of an efficient immune response. DCs are unique in their ability to induce primary immune responses by priming and cells, allowing the establishment of immunological memory (27-29). Thus, interference with DC function could promote viral spread by paralyzing the adaptive immune system. activating naive 1 hittp://onlinelibrary.wiley.com/doi/10.1111/.1600-0463.2009.02449.x/full 12/4201 Dendritic cells in cytomegalovirus infection: viral evasion and host countermeasures - RO... Page 5 of 30 Human DC subsets DCs reside in most tissues in the body, and a multitude of subsets have been identified in human peripheral tissues, secondary lymphoid organs and peripheral blood. The scarcity of DCs and DC- specific markers in peripheral tissues limited functional studies of these subsets, whereas the generation of DCs by prolonged culture of precursors from blood or bone marrow facilitated the characterization of large numbers of cells. Depending on the culture conditions, CD34* hematopoietic progenitor cells, containing precursors for all hematopoietic cell types, can give rise to DCs with characteristics of interstitial DCs (dermal DCs) or Langerhans cells, respectively (30). Furthermore, peripheral blood monocytes can be developed into so-called monocyte-derived DCs (moDCs) in vitro [reviewed in (31)]. ‘The first developmental models of DCs were based on such in vitro-cultured cells and indicated that DCs in lymphoid organs represent the end stage of a stepwise differentiation and migration process, initiated and completed only upon inflammation (32-35). Subset-specific markers or marker combinations allowed, however, the two major DC populations in peripheral blood to be directly identified. The so-called plasmacytoid DCs (pDCs), named according to theit morphology when freshly isolated, and CD11¢* myeloid DCs reciprocally express CD11e, share a lack of lineage markers and a 2 high expression of HLA-DR (36-38). pDCs are specifically characterized by ther high expression of D123 (interleukin-3 receptor @) in peripheral blood, secondary lymphoid organs and bone marrow, and constitute a separate cell lineage (39). The two peripheral blood DC subsets differ in the expression of Toll-like receptors (TLRs) (40, 41), function, and in the routes followed to enter secondary lymphoid tissues (42, 43). The ease of isolation has facilitated numerous in vitro studies of these cells. The abi to achieve pure populations and rapidly induce maturation in cell culture, increases the validity of in vitro findings for the in vivo situation. Although a subset equivalent to human pDCs has been identified in the mouse (44), other DC subsets in humans and mice do not directly correspond. Held together with the fact that MCMV and HCMV are highly species specific, inference from mouse models to humans should be made with caution. In the following, we will discuss the literature on how HCMV interacts with moDCs and peripheral blood DCs. moDCs in HCMV infection ‘The majority of studies of the interaction between DCs and HCMV focus on moDCs, which can be infected by fresh isolates of HCMV (45, 46), a process partially relying on viral binding to DC-SIGN (42). Infection was described to result in a slight increase in the co-stimulatory molecules CD40, CD80 and CD86, a concomitant downregulation of both MHC class I and II (48) and a rapid maturation of those immature DCs surviving infection. Interestingly, in the same study, mature DCs infected with HCMYV were found to acquire the capacity to kill PBMC or T-cell lines by expression of CD9SL (FasL) and TRAIL, as well as to suppress T-cell proliferation by non-deletional mechanisms. A second report, http://onlinelibrary.wiley.com/doi/10.1111/}.1600-0463.2009.02449.x/full 12/4/2011 Dendritic cells in cytomegalovirus infection: viral evasion and host countermeasures - RO... Page 6 of 30 using slightly different viral strains, instead described a decrease in co-stimulatory molecules, inhibition of DC maturation and diminished IL-12 or TNF-2. production in response to LPS or CD40L, but corroborated the findings on inefficient induction of T-cell proliferation by infected DCs (49). Similar findings were obtained for Langerhans cell-type DCs although in that lineage mature DCs were more susceptible to infection (50). There is some evidence that inefficient stimulation of allogeneic lymphocytes could play a role in vivo, as DCs generated from PBMCs of immunocompetent patients with symptomatic HCMV disease were reported to be impaired in that regard (51). ‘A recent study investigated effects of the HCMV protein UL18 on DC phenotype and function. Similar 10 earlier reports that looked at the functional capacity of productively infected DCs, a weaker induction of T-cell proliferation in allogeneic assays was observed when UL18 was present during CD401~ induced maturation. Binding of a UL18 fusion protein to immature moDCs resulted in the expression of CD83 but not other maturation markers, increased IL-10 and IL-6 secretion, and an impaired migration in response to the chemokine RANTES (52). Elevated local IL-10 concentrations could affect DC trafficking during HCMV infection, because previous studies indicated that IL-10 can induce the expression of unresponsive, inflammatory chemokine receptors on DCs (53). Interestingly, CD83 is released by infected mature DCs in a soluble form that inhibits ‘T-cell proliferation. Uninfected DCs displayed the same impairment when exposed to a CD83-containing supernatant, suggesting a paracrine effect of HCMV infection on adjacent, uninfected DCs (54). HCMV has also been described to induce CCL3/MIP-1a, CCL4/MIP-1P and CCLS/RANTES, leading to downregulation of CCRI and CCRS receptors on immature DCs, limiting their migratory capabilities (55). The multi-layered subversion of moDC function might also reflect their importance as a site of latency and the role that moDC maturation plays in viral reactivation (56) (Eig. 1). Figure 1. Human cytomegalovirus infection impairs the function of monocyte-derived dendritic cells (moDCs). Infection of immature DCs leads to increased cell death and altered chemokine receptor expression, leading to altered migration properties. Surviving DCs mature rapidly and, besides other phenotypical changes, upregulate FasL, and CD83. Infected DCs inhibit T-cell proliferation by deletional and non-deletional mechanisms. Download figure to PowerPoint Peripheral blood DCs in HCMV infection In light of the impressive array of immuno-evasive viral gene products, including those compromising hutp://onlinelibrary.wiley.com/doi/10.1111.1600-0463.2009.02449.x/full 12/4201 Dendritic cells in cytomegalovirus infection: viral evasion and host countermeasures - RO... Page 7 of 30 the function of moDCs, itis conceptually hard to understand why HCMY is so well controlled by the human immune system in healthy individuals. pDCs are the major source of type I interferons (IFN-a/B) ‘upon viral infection in humans (57, 58) as well as in the mouse (44, 59). IFN-2 is a potent activator of anti-viral responses both in innate and in acquired immune responses (60. 61). Upon acute MCMV infection, pDCs produce IFN-a/B (62-64) that limits viral replication and spread by various mechanisms (65). This response was described to be MyD88 dependent and mediated via TLR9 ligation (66). Other reports have questioned the exclusive role of TLR9 (67), given that in vivo depletion of pDCs does not decrease IL-12 levels or increase viral titers in the spleen (64). A recent study described partially redundant functions of TLR9 with TLR7 in the innate response against MCMV, reconciling the earlier findings (68). For a more detailed review of innate signaling pathways, we refer to the article by Rasmussen and colleagues in this issue. ‘The asymptomatic course of HCMV infection in healthy humans, and the murine data showing successful immunity to MCMV, indicated that DC subsets other than moDCs are instrumental for viral host defense. This prompted us to study the role of human peripheral blood DCs in HCMV infection. We could demonstrate that CD11¢* DCs can be infected with clinical isolates of HCMV while pDCs ‘were resistant (69). However, another report indicated that pDCs are susceptible to non-permissive infection (70). Both studies used the TB40/E strain for infection and staining for HOMV IE antigen as read-out, and demonstrated the production of large amounts of type I IFNs after exposure to HCMV (69, 70). The discrepancy could, however, possibly be explained by the lower purity of the pDC population in the study by Varani and colleagues, as only very low percentages of isolated cells were infected and an increase in MOI did not increase the rate of infection. Interestingly, we also showed that CDI 1e* DCs produce large amounts of type I IFN when exposed to HCMV (69). In agreement with this, murine non-pDCs have subsequently been described to produce substantial amounts of type I IFNs under certain circumstances (71). We further demonstrated that neutralizing antibodies against type I IFNs and blocking antibodies against the type I IFN receptor increased the rate of infection in CD1 1c" cells, but did not affect infection of pDCs (69). This could either imply constitutive low-level production of IFN- «a, which was not blocked by our antibody cocktail, or could simply reflect the absence of receptors required for viral entry on the cell surface of pDCs. Interestingly, a recent report indicated that pDCs obtained from human tonsils, potentially a decisive subset during primary infection, are permissive for HCMV infection (72), but confirmed our results regarding the resistance of pDCs derived from peripheral blood. We further demonstrated that in contrast to moDCs, CD1 1e* DCs upregulated MHC class I and II as well as the maturation marker CD83 upon infection, an effect partially dependent on type I TENs (69). The basis for the molecular recognition of HCMV and the consecutive production of type I IFNs remains insufficiently understood. While in mice TLR9 plays an important role, this TLR is not expressed on human CDI 1c* DCs (40), which instead secrete IFN-a in response to TLR3 ligation. However, double-stranded RNA, the prototypical TLR3 ligand, is not synthesized during the replication cycle of HCMY, raising the question of whether other viral components such as gB could serve as novel hittp://onlinelibrary.wiley.com/doi/10.1111.1600-0463.2009.02449.x/full 12/4/2011 Dendritic cells in cytomegalovirus infection: viral evasion and host countermeasures - RO... Page 8 of 30 ‘TLRS ligands (73,74). Importantly, infected CD1 1c" cells retained the ability to stimulate CD4* and CD8* T-cell proliferation in allogeneic cultures (69). Our in vitro data provide a rational explanation for the beneficial effect of IEN treatment for the prevention of HCMV disease in early clinical trials (61, 75) and clearly show that the viral mechanisms for immunosuppression of moDCs are not operational in CDI 1¢* DCs. The data further suggested that pDCs and CDI 1c DCs are important for an efficient immune response to HCMV. Infection with HCMV, mostly due to re-activation of the latent virus, represents a major clinical problem in transplanted patients, Patients treated with immunosuppressants, such as steroids, have low numbers of DCs in blood (76, 77). These findings were extended by our observation that renal transplant recipients had relatively lower frequencies of pDCs and CD11¢* DCs among their PBMCs than healthy individuals (69). The results further suggested an important role for the two peripheral blood DC subsets in the induction of memory responses counteracting HCMY re-activation. In the mouse, pDCs efficiently drive the expansion and terminal ThI polarization of recall responses (78). In a subsequent study, we investigated whether pDCs and CD11¢* DCs in humans activate HCMV-specifie memory 1 cells. Both DC populations induced strong T-cell proliferation (79), whereas the T-cell cytokine profile ‘was strikingly different only a few hours after DC encounter. A large fraction of CD4* memory T cells produced IL-10 in the pDC co-cultures, whereas CD1 1e* DCs predominantly induced IFN-Y. The IL- 10-produeing T-cells suppressed antigen-induced T-cell proliferation in an IL-10-dependent manner, and acquired the ability to produce high levels of IFN-y following re-stimulation. PDCs accumulate at inflammatory sites (80-82), where they encounter virus and memory T cells. By promoting IL-10 production from antigen-specific T cells in the early phase of the response, the function and maturation of other DCs are suppressed. This is advantageous to prevent presentation of antigens irrelevant to the infection, Secretion of type I IFNs by pDCs may serve a similar purpose as IL-10. The cytokine has anti- proliferative effects on T cells and has been shown to limit bystander T-cell activation (83, 84). Ag- specific CD8* T cells may escape the anti-proliferative effects of type I IFNs by TCR-mediated downregulation of STATI (85). Furthermore, only T cells with the highest receptor affinities might be activated by pDCs, because they generally have lower levels of co-stimulatory molecules and HLA class ules than other DC subsets. Taken together, it is tempting to suggest that a first-line anti-viral defense by pDCs might serve to secure the antigen specificity of the immune response and limit immune I mol activation, potentially leading to autoimmunity. This idea is supported by our data showing that pDCs were superior relative to CDI 1c* DCs in their ability to selectively expand cytokine-producing T cells (79) ig..2). Figure 2. Human cytomegalovirus (HCMV) activates peripheral blood dendritic cells (DCs). CD11¢* and plasmacytoid DCs (pDCs) respond to exposure to HOMV with the production of interferon (IFN)-a/f, but only http://onlinelibrary.wiley.com/doi/10.1111.1600-0463.2009.02449.x/full 12/4/2011 Dendritic cells in cytomegalovirus infection: viral evasion and host countermeasures - RO... Page 9 of 30 CD11e* DCs can be infected by HCMV. In contrast to moDCs, both peripheral blood DC subsets retain the ability to stimulate T cells. Both subsets induce T-cell proliferation but distinct cytokine profiles. Upon challenge with HCMV, antigen-specific CD4* T cells (green) co-cultured with CD11c* cells respond mainly with IFN-y secretion, while those induced by plasmacytoid DCs (pDCs) primarily secrete IL-10 in the early phase of the response, IL-10 limits activation of bystander T cells (blue) by suppression of antigen- presenting cells, Type I IFNs also inhibit T-cell proliferation and bystander activation. Thus, viral activation of pDC in the first line of defense might serve to focus the adaptive immune response to antigen-specific T cells while limiting the risk of autoimmunity. Download figure to PowerPoint NK cells and HCMV While the pronounced reduction of cell surface MHC on HCMV-infected cells could solve the challenge of T-cell recognition, it could theoretically create a new problem for the virus, i.e. an increased susceptibility to NK cells. NK cells preferentially kill targets with decreased or absent MHC class I expression ~a concept known as ‘missing-self recognition’ (86). Indeed, the clinical presentation of patients deficient in NK cells supports a role in the early control of herpes virus infections (87-89), including HCMV and consequently, several NK-cell evasins have been described, some of which interfere with NK-cell-activating pathways (90-92) while others have been suggested to deliver inhibitory signals substituting for the lack of inhibitory MHC class I molecules after infection (93, 94). NK-DC cross-talk NK cells and DCs are among the first immune cells to encounter a viral challenge. Their instant response, often characterized by the secretion of large amounts of cytokines, has a direct effect on the infection itself but is also pivotal in shaping consecutive adaptive immune responses. Itis therefore perhaps not surprising that both cell types can engage in an intense and complex cross-talk, which has been shown to contribute substantially to successful host defense, and we will discuss MCMV asa prototypical example. Depending on the experimental system, the result of the interaction between DCs and NK cells ranges from mutual activation over the promotion of DC maturation to the elimination of http://onlinelibrary.wiley.com/doi/10.111 1/).1600-0463.2009.02449.x/full 12/4/2011 Dendritic cells in cytomegalovirus infection: viral evasion and host countermeasures - ..._ Page 10 of 30 DCs by NK cells. (Fig. 3) Figure 3. Murine cytomegalovirus (MCMY) infection profoundly affects the dendritic cell (DC)-natural killer (NK) cell cross-talk. Barly effects of MCMV infection on murine DCs include downregulation of co-stimulatory molecules and major histocompatibility complex (MHC) class I and Il as well as a reduction in IL-2 and IL-12 production, which in tum leads to impaired T-cell activation and proliferation. However, DCs activate NK cells via secretion of interferon (IFN)-a. and upregulation, of ligands for the NK cell receptor NKG2D. NK cells in turn induce DC maturation by releasing IFN-y, tumor necrosis factor (TNF)-a and granulocyte macrophage- colony stimulating factor (GM-CSF). Several days post, infection, the expansion of a Ly49H* NK cell subset, which recognizes the viral glycoprotein m157, is promoted by DC-derived I-18 and IL-12 and contributes decisively to clearance of the infection in certain mouse strains. Download figure to PowerPoint Invitro studies of the cross-talk between DCs and NK cells have been useful to dissect the molecular interactions between both cell types and support a role for cytokines as well as cell contact-dependent signals (95): secretion of IL-12 and IL-18 by DCs considerably enhances IFN-y production in NK cells, although it has been suggested that in bacterial infections, IL-2 can serve a similar function (96). In secondary lymphoid organs, DC-derived IL-12 and IL-15 have been described as key cytokines for IFN- secretion and NK-cell proliferation, respectively (97). With regard to the secretion of IL-12, itis interesting to note that the formation of an immunological synapse between DCs and NK cells is required (98), implying that additional modulation of adhesion molecules during infection is likely to affect this cross-talk. Depending on the maturation stimulus, NK-cell activation by DCs does not, however, always depend on IL-12. If DCs are matured with type I IFNs instead of LPS, NK-cell activation may occur via ligands for activating NK-cell receptor NKG2D (99). Another report suggests ‘an important role for membrane-bound IL-15 on DCs for the survival and proliferation of human NK cells in secondary lymphoid tissue (100). This finding was corroborated in a recent mouse study proposing that NK-cell activation can depend entirely on the trans-presentation of IL-15 on DCs in secondary lymphoid organs (101). In another murine model, the injection of mature DCs led to the CXCR3-dependent recruitment of NK cells to lymph nodes, where IFN-Y secretion correlated with the http://onlinelibrary.wiley.com/doi/10.1111.1600-0463.2009.02449.x/full, 12/4/2011 Dendritic cells in cytomegalovirus infection: viral evasion and host countermeasures -..._ Page 11 of 30 induction of Th1 responses (102). A recent in vivo study of Listeria infection elegantly demonstrated the hierarchy of innate immune cell activation with CD11c* DCs orchestrating a largely MyD88-dependent, IL-12- and IL-18-mediated clustering of NK cells around infected foci and their consecutive IFN-Y production (103). Conversely, NK cells are also able to profoundly affect DC functions. The high susceptibility of immature DCs to NK-cell-mediated lysis is intriguing (104-106), an interaction primarily mediated via the activating NK-cell receptor NKp30 and its, as yet unknown, ligand on DCs (107, 108). The relative resistance of mature DCs has been ascribed to higher expression levels of MHC class J, in particular, the non-classical molecule HLA-E (109). Another report suggested that the expression of PI9, an intracellular inhibitor of granzyme B, which is upregulated by DCs after maturation, confers protection from lysis (110). While the killing of mature DCs by NK cells could be interpreted as a negative feedback loop, limiting and terminating ongoing immune responses, the lysis of immature DCs could possibly ensure that only DCs that have encountered antigen participate in a response. However, this hypothesis remains to be tested, and under certain circumstances, the interaction between immature DCs and NK cells actually does not result in DC lysis but instead in enhanced DC maturation (107, 111-113). Likewise, in a tumor setting, it has been shown that activated NK cells prime DCs to produce TL-12, resulting in the induction of highly protective CD8 T-cell memory responses (114). Whether activation or killing is the result of their interaction seems, at least in part, to depend on the ratio at which the NK~DC encounter takes place. Fewer data are available for NK-cell interactions with pDCs, although again, NK-cell activation and induction of pDC maturation are possible outcomes (115, 116), while CD4* T cells can enhance this cross-talk in an IL-2-dependent manner (117). Notably, pDCs seem to be resistant to NK lysis (118). MCMV as a model system The mouse model for CMV infection has proven to be a valuable tool to assess in vivo aspects of the host-pathogen relationship, including the interactions between DCs and NK cells, in CMV infection. Even though there is no direct homology between these highly species-restricted viruses, MCMV and HCMV display a high degree of functional analogies, including a similar course of the antiviral immune response. Similar to the findings with HCMY, the infection of CDI 1¢* DCs by MCMV results in impaired antigen uptake, an altered DC phenotype and a loss of responsiveness to maturation stimuli (19). Functionally, the capacity for IL-2 and IL-12 seeretion as well as for allostimulation is reduced. However, before this transient virally induced immunosuppression is fully established, DCs have sufficient time to initiate early immune responses by producing IFN-a, IL-12 and IL-18 and expressing http://onlinelibrary.wiley.com/doi/10.1111/j.1600-0463.2009.02449.x/full 12/4/2011 Dendritic cells in cytomegalovirus infection: viral evasion and host countermeasures -..._ Page 12 of 30 ‘NK-cell-activating ligands (120). Notably, adoptive transfer of DCs exposed to MCMV contributed to control of the infection by activating NK cells. Another study demonstrated that the presence of CD8a.* DCs in the spleen is required for the late expansion of Ly49H* NK cells, a subset crucial for controlling of the infection in certain mouse strains (121), while conversely the proliferating NK cells maintain the presence of splenic CD8a.* DCs (122). CONCLUDING REMARKS n this review, we have highlighted multiple examples of how HCMY infection in humans and mice subverts the immune response to the viral challenge. In many cases, evasion mechanisms are of pressive efficiency when studied in the context of reduetionistic in vitro systems. This is in sharp contrast to the undeniable fact that HCMV is well controlled by a healthy immune .ystem, Accordingly, a comprehensive study analyzing the global T-cell response to overlapping, septides covering the entire HCMV genome concluded that 5% of total peripheral blood CD4 and CD8 [ cells and 10% in the memory compartment recognize a surprisingly broad range of HCMY epitopes 1123). A remarkable result, given the array of viral immune evasions, directed against the MHC class I intigen presentation pathway, but at the same time in accordance with the unproblematic course of most CMV infections. In the murine system, viral gene products targeting MHC class I antigen presentation {id not affect the CD8* T-cell response in vivo when comparing a wild-type virus with a mutant leficient in several immuno-evasins. No differences were observed in terms of the size, kinetics, sierarchy of immunodominance, memory inflation or transition to chronic infection (124. 125). cross-presentation of viral antigens by uninfected DCs has been suggested to bypass viral evasion nechanisms (126, 127) and ensure efficient CD8* T-cell priming in spite of the disrupted MHC class T intigen presentation pathway in infected cells. Other determinants presumably limiting the efficiency of ‘iral escape mechanisms in vivo ate tissue-specific factors (128) and MHC polymorphisms, allowing the sscape from allele-specific evasins (129). While numerous reports describe an impairment of moDCs, potentially limiting T-cell priming, we could demonstrate that other DC subsets, such as pDCs, remain ‘lly functional after exposure to HCMY, and presumably contribute to the successful control of HCMV n the overwhelming part of the population, The general focus on the acute, lytic phase of CMV infection might, however, unnecessarily limit our view of the pathogen-host relationship. It has recently been suggested that viral evasins could, beyond heir obvious role, contribute to fine tuning the quality, quantity and kinetics of the immune response 50 hat an optimal viral load would facilitate the transition to persistence/latency (130). Latency itself could ye a goal not only for CMV but also for the host: an intriguing study questioned our traditional view that complete clearance of herpesvirus infections would be desirable (131). In a mouse model, the presence http://onlinelibrary.wiley.com/doi/10.1111.1600-0463.2009.02449.x/full 12/4/2011 Dendritic cells in cytomegalovirus infection: viral evasion and host countermeasures -..._ Page 13 of 30 of latent herpesviruses conferred protection from bacterial infections, suggesting that the long co- evolution between CMV and its host, often seen as a molecular race of arms, could actually benefit both sides. REFERENCES 1 Mocarski ESS, Shenk T, Pass RF. Cytomegaloviruses. In: BernardN, FieldsDMK, HowleyPM, GriffinDE, LambRA, MartinMA, editors. Fields Virology, Sth ed, Philadelphia, PA: Lippincott Williams & Wilkins, 2006:2701-72. Vyas JM, Van der Veen AG, Ploegh HL. The known unknowns of antigen processing and presentation, Nat Rev 2008;8:607-18. CrossRef, PubMed, CAS, Web of Science® Times Cited: 30 ‘Ackerman AL, Cresswell P. Cellular mechanisms governing cross-presentation of exogenous antigens, Nat Immunol 2004;5:678-84. CrossRef, PubMed, CAS, Web of Science® Times Reddehase MJ, Mutter W, Munch K, Buhring HJ, Koszinowski UH. CD8-positive T Iymphoeytes specific for murine cytomegalovirus immediate-early antigens mediate protective immunity. J Virol 1987;61:3102-8. PubMed, CAS, Web of Science® Times Cited: 279 Riddell SR, Watanabe KS, Goodrich JM, Li CR, Agha ME, Greenberg PD. Restoration of viral immunity in immunodeficient humans by the adoptive transfer of T cell clones. Science 1992;257:238-41. CrossRef, PubMed, CAS, Web of Science® Times Cited: 668, ADS Kapp M, Tan SM, Einsele H, Grigoleit G. Adoptive immunotherapy of HCMV infection. Cytotherapy 2007;9:699-711. CrossRef, PubMed, CAS, Web of Science® Times Cited: | Yewdell JW, Hill AB. Viral interference with antigen presentation. Nat Immunol 2002;3:1019- 25, CrossRef, PubMed, CAS, Web of Science® Times Cit : 110, hittp://onlinelibrary.wiley.com/doi/10.111 1/j.1600-0463.2009.02449.x/full 12/4/2011 Dendritic cells in cytomegalovirus infection: viral evasion and host countermeasures 10 ul 12 14 15 Page 14 of 30, Gilbert MJ, Riddell SR, Plachter B, Greenberg PD. Cytomegalovirus selectively blocks antigen processing and presentation of its immediate-early gene product. Nature 1996;383:720-2. CrossRef, PubMed, CAS, Web of Science® Times Cited: 177, ADS Wiertz EJ, Jones TR, Sun L, Bogyo M, Geuze HJ, Ploegh HL. The human cytomegalovirus USII gene product dislocates MHC class I heavy chains from the endoplasmic reticulum to the cytosol. Cell 1996;84:769-79. CrossRef, PubMed, CAS, Web of Science® Times Cited: 656 Wiertz EJ, Tortorella D, Bogyo M, Yu.J, Mothes W, Jones TR, et al. Sec61-mediated transfer ofa membrane protein from the endoplasmic reticulum to the proteasome for destruction Nature 1996;384:432-8. CrossRef, PubMed, CAS, Web of Science® Times Cited: 698, ADS Machold RP, Wiertz EJ, Jones TR, Ploegh HL. The HCMV gene products USI1 and US2 differ in their ability to attack allelic forms of murine major histocompatibility complex (MHC) class Theavy chains. J Exp Med 1997;185:363-6. CrossRef, PubMed, CAS, Web of Science® Times Cited: 87 Tomazin R, Boname J, Hegde NR, Lewinsohn DM, Altschuler Y, Jones TR, et al. Cytomegalovirus US2 destroys two components of the MHC elass II pathway, preventing recognition by CD4* T cells. Nat Med 1999;5:1039-43. CrossRef, PubMed, CAS, Web of Science® Times Cited: 137 Ben-Arieh SV, Zimerman B, Smorodinsky NI, Yaacubovicz M, Schechter C, Bacik I, et al ‘Human cytomegalovirus protein US2 interferes with the expression of human HFE, a nonclassical class I major histocompatibility complex molecule that regulates iron homeostasis. J Virol 2001;75:10557-62. CrossRef, PubMed, CAS, Web of Science® Times Cited: 36 Jones TR, Wiertz EJ, Sun L, Fish KN, Nelson JA, Ploegh HL. Human cytomegalovirus US3 impairs transport and maturation of major histocompatibility complex class I heavy chains. Proc Natl Acad Sei USA 1996;93:11327-33. CrossRef, PubMed, CAS, Web of Science® Times Cited: 245, ADS Hegde NR, Tomazin RA, Wisner TW, Dunn C, Boname JM, Lewinsohn DM, et al. Inhibition of HLA-DR assembly, transport, and loading by human cytomegalovirus glycoprotein US3: a http://onlinelibrary.wiley.com/doi/10.1111/}.1600-0463.2009.02449.x/full 12/42011 Dendritic cells in cytomegalovirus infection: viral evasion and host countermeasures -... Page 15 of 30 16 novel mechanism for evading major histocompatibility complex class II antigen presentation. J Virol 2002;76:10929-41. PubMed, CAS, Web of Science® Times Cited: 38 ‘Ahn K, Gruhler A, Galocha B, Jones TR, Wiertz EJ, Ploegh HL, et al. The ER-luminal domain of the HCMV glycoprotein US6 inhibits peptide translocation by TAP. Immunity 1997;6:613— CrossRef, PubMed, CAS, Web of Science® Times Cited: 261 18 19 20 21 2 23 Ulbrecht M, Hofmeister V, Yuksekdag G, Ellwart JW, Hengel H, Momburg F, et al. HCMV glycoprotein US6 mediated inhibition of TAP does not affect HLA-E dependent protection of K-562 cells from NK cell lysis. Hum Immunol 2003;64:231~7. CrossRef, PubMed, CAS, Web of Science® Times Cited: 12 Fruh K, Ahn K, Djaballah H, Sempe P, Van Endert PM, Tampe R, et al. A viral inhibitor of ‘peptide transporters for antigen presentation. Nature 1995;375:415-8. CrossRef, PubMed, CAS, Web of Science® Times Cited: 382, ADS Furman MH, Dey N, Tortorella D, Ploegh HL. The human cytomegalovirus USO gene product delays trafficking of major histocompatibility complex class I molecules. J Virol 2002;76:11753-6 CrossRef, PubMed, CAS, Web of Science® Times Cited: 37 ‘Trgovcich J, Cebulla C, Zimmerman P, Sedmak DD. Human eytomegalovirus protein pp71 disrupts major histocompatibility complex class I cell surface expression. J Virol 2006;80:951-63. CrossRef, PubMed, CAS, Web of Science® Times Cited: 8 Kotenko SV, Saccani S, Izotova LS, Mirochnitchenko OV, Pestka S. Human cytomegalovirus harbors its own unique IL-10 homolog (cmvIL-10). Proc Natl Acad Sci USA 2000;97:1695- 700. CrossRef, PubMed, CAS, Web of Science® Times Cited: 198, ADS Kledal TN, Rosenkilde MM, Schwartz TW. Selective recognition of the membrane-bound CX3C chemokine, fractalkine, by the human cytomegalovirus-encoded broad-spectrum receptor US28. FEBS Lett 1998;441:209-14. CrossRef, PubMed, CAS, Web of Science® Times Cited: 84 hitp://onlinelibrary.wiley.com/doi/10.1111.1600-0463.2009.02449.x/full 12/4/2011 Dendritic cells in cytomegalovirus infection: viral evasion and host countermeasures - ..._ Page 16 of 30 24 25 26 27 28 29 30 31 Penfold ME, Dairaghi DJ, Duke GM, Saederup N, Mocarski ES, Kemble GW, et al. Cytomegalovirus encodes a potent alpha chemokine. Proc Natl Acad Sci USA 1999;96:9839- 44, CrossRef, PubMed, CAS, Web of Science® Times ited: 165, ADS Goldmacher VS, Bartle LM, Skaletskaya A, Dionne CA, Kedersha NL, Vater CA, et al. A eytomegalovirus-encoded mitochondria-localized inhibitor of apoptosis structurally unrelated 10 Bel-2. Proc Natl Acad Sci USA 1999;96:12536—41 CrossRef, PubMed, CAS, Web of Science® Times Cited: 213, e iS S Skaletskaya A, Bartle LM, Chittenden T, McCormick AL, Mocarski ES, Goldmacher VS. A cytomegalovirus-encoded inhibitor of apoptosis that suppresses caspase-8 activation. Proe NI Acad Sci USA 2001;98:7829-34. CrossRef, PubMed, CAS, Web of Science® Times Cited: 139, ADS Mocarski ES Jr. Immunomodulation by cytomegaloviruses: manipulative strategies beyond evasion. Trends Microbiol 2002;10:332-9. PubMed, CAS, Web of Science® Times Cited: 117 Steinman RM. The dendritic cell system and its role in immunogenicity. Annu Rev Immunol 1991;9:271-96. CrossRef, PubMed, C. ;, Web of Science® Times Cited: 3420 Banchereau J, Steinman RM. Dendritic cells and the control of immunity. Nature 1998;392:245-52. CrossRef, PubMed, CAS, Web of Science® Times Cited: 6685, ADS Hart DN. Dendritic cells: unique leukocyte populations which control the primary immune response, Blood 1997;90:3245-87. PubMed, CAS, Web of Science® Times Cited: 999 Caue: C, Vanbervliet B, Massacrier C, Dezutter-Dambuyant C, De Saint-Vis B, Jacquet C, et al, CD34* hematopoietic progenitors from human cord blood differentiate along two independent dendritic cell pathways in response 10 GM-CSF+TNF alpha. J Exp Med 1996;184:695-706, CrossRef, PubMed, C. Web of Science® Times Cited: 626 Peters JH, Gieseler R, Thiele B, Steinbach F. Dendritic cells: from ontogenetic orphans to http://onlinelibrary.wiley.com/doi/10.1111.1600-0463.2009.02449.x/full 12/4/2011 Dendritic cells in cytomegalovirus infection: viral evasion and host countermeasures -... Page 17 of 30 32 33 34 36 37 38 39 myelomonocytic descendants. Immunol Today 1996;17:273-8. Fearon DT, Locksley RM. The instructive role of innate immunity in the acquired immune response. Science 1996;272:50-3. CrossRef, PubMed, CAS, Web of Science® Times Cited: 968, ADS. Lanzaveechia A. Mechanisms of antigen uptake for presentation. Curr Opin Immunol 1996;8:348-54. CrossRef, PubMed, CAS, Web of Science® Times Ci Austyn IM. New insights into the mobilization and phagocytic activity of dendritic cells. J Exp Med 1996;183:1287-92. CrossRef, PubMed, CAS, Web of Science® Times Cited: 293 Ibrahim MA, Chain BM, Katz DR. The injured cell: the role of the dendritic cell system as a sentinel receptor pathway. Immunol Today 1995;16:181-6. PubMed, CAS, Web of Science Times Cited: 127 Grouard G, Rissoan MC, Filgueira L, Durand I, Banchereau J, Liu ¥J. The enigmatic plasmacytoid T cells develop into dendritic cells with interleukin (IL)-3 and CD40-ligand. J Exp Med 1997;185:1101-11. CrossRef, PubMed, CAS, Web of Science® Times Cited: 616 Cameron PU, Lowe MG, Sotzik F, Coughlan AF, Crowe SM, Shortman K. The interaction of ‘macrophage and non-macrophage tropic isolates of HIV-1 with thymic and tonsillar dendritic cells in vitro. J Exp Med 1996;183:1851-6. CrossRef, PubMed, CAS, Web of Science ® Times Cited: 49 O'Doherty U, Peng M, Gezelter S, Swiggard WJ, Betjes M, Bhardwaj N, et al. Human blood contains two subsets of dendritic cells, one immunologically mature and the other immature. Immunology 1994;82:487-93. PubMed, CAS, Web of Science® Times Cited: 431 Obveus J, BitMansour A, Warnke R, Thompson PA, Carballido J, Picker LJ, et al. Dendritic cell ontogeny: a human dendritic cell lineage of myeloid origin. Proc Natl Acad Sei USA 1997;94:12551-6. PubMed, CAS, Web of Science® Times C 295 hitp:/onlinelibrary.wiley.com/doi/10.1111}.1600-0463.2009.02449.x/full 12/4/2011 Dendritic cells in cytomegalovirus infection: viral evasion and host countermeasures -... Page 18 of 30 4 2 4B 44 45 46 47 40 Kadowaki N, Ho S, Antonenko S, Malefyt RW, Kastelein RA, Bazan F, et al. Subsets of human dendritic cell precursors express different toll-like receptors and respond to different microbial antigens. J Exp Med 2001;194:863-9 CrossRef, PubMed, CAS, Web of Science® Times Cited: 875 Jarrossay D, Napolitani G, Colonna M, Sailusto F, Lanzavecchia A. Specialization and complementarity in microbial molecule recognition by human myeloid and plasmacytoid dendritic cells. Eur J Immunol 2001;31:3388-93. Direct Link: o Abstract © Full Article (HTML) o PDF(109K) o References Yoneyama H, Matsuno K, Zhang Y, Nishiwaki T, Kitabatake M, Ueha S, et al. Evidence for recruitment of plasmacytoid dendritic cell precursors to inflamed lymph nodes through high endothelial venules, Int Immunol 2004;16:915~28. Cros PubMed, CAS, Web of Science® Times Cited: 107 Liu YJ. IPC: professional type | interferon-producing cells and plasmacytoid dendritic cell precursors. Annu Rev Immunol 2005;23:275-306. PubMed, CAS, Web of Science® Times Cited: 409 Nakano H, Yanagita M, Gunn MD. CDI 1e(+)B220(+)Gr-I(+) cells in mouse lymph nodes and spleen display characteristics of plasmacytoid dendritic cells. J Exp Med 2001;194:1171-8. CrossRef, PubMed, CAS, Web of Science® Times Cited: 391 Hahn G, Jores R, Mocarski ES. Cytomegalovirus remains latent ina common precursor of dendritic and myeloid cells. Proc Natl Acad Sci USA 1998;95:3937-42. CrossRef, PubMed, CAS, Web of Science® Times Cited: 209, ADS Beck K, Meyer-Konig U, Weidmann M, Nern C, Hufert FT. Human cytomegalovirus impairs dendritic cell function: a novel mechanism of human cytomegalovirus immune escape. Bur J Immunol 2003;33: 1528-38. PubMed, CAS, Web of Science® Times Cited: 33 Halary F, Amara A, Lortat-Jacob H, Messerle M, Delaunay T, Houles C, et al. Human http://onlinelibrary.wiley.com/doi/10.1111.1600-0463.2009.02449.x/full 12/4/2011 Dendritic cells in cytomegalovirus infection: viral evasion and host countermeasures -... Page 19 of 30 48 49 50 31 52 53 55 cytomegalovirus binding to DC-SIGN is required for dendritic cell infection and target cell trans-infection. Immunity 2002;17:653-64. CrossRef, PubMed, CAS, Web of Science® Times Ci 157 Raftery MI, Schwab M, Eibert SM, Samstag ¥, Walczak H, Schonrich G. Targeting the function of mature dendritic cells by human cytomegalovirus: a multilayered viral defense strategy. Immunity 2001;18:997-1009. PubMed, CAS, Web of Science® Times Cited: 112 Moutafisi M, Mehl AM, Borysiewicz LK, Tabi Z. Hunan cytomegalovirus inhibits maturation and impairs function of monocyte-derived dendritic cells. Blood 2002;99:2913-21 CrossRef, PubMed, CAS, Web of Science® Times Cited: 109 Hertel L, Lacaille VG, Strobl H, Mellins ED, Mocarski ES. Susceptibility of immature and mature Langerhans cell-type dendritic cells to infection and immunomodulation by human cytomegalovirus. J Virol 2003;77:7563-74. CrossRef, PubMed, CAS, Web of Science® Times Cited: 47 Prascaroli G, Varani 8, Mastroianni A, Britton S, Gibellini D, Rossini G, et al. Dendritic c function in cytomegalovirus-infected patients with mononucleosis. J Leukoe Biol 2006;79:932— 40. CrossRef, PubMed, CAS, Web of Science® Times Cited: 7 Wagner CS, Walther-Jallow L, Buentke E, Ljunggren HG, Achour A, Chambers BJ. Human cytomegalovirus-derived protein ULI8 alters the phenotype and function of monocyte-derived dendritic cells. J Leukoe Biol 2008;83:56-63. CrossRef, PubMed, CAS, Web of Science® Times Cited: 9 D'Amico G, Frascaroli G, Bianchi G, Transidico P, Doni A, Vecchi A, et al. Uncoupling of inflammatory chemokine receptors by IL-10: generation of functional decoys. Nat Immunol 2000;1:387-91. PubMed, CAS, Web of Science® Times Cited: 150 Senechal B, Boruchov AM, Reagan JL, Hart DN, Young JW. Infection of mature monocyte- derived dendritic cells with human cytomegalovirus inhibits stimulation of T-cell proliferation via the release of soluble CD83. Blood 2004;103:4207-I5. CrossRef, PubMed, CAS, Web of Science® Times Cited: 27 http://onlinelibrary.wiley.com/doi/10.1111.1600-0463.2009.02449.x/full 12/4/2011 Dendritic cells in cytomegalovirus infection: viral evasion and host countermeasures -..._ Page 20 of 30 56 37 59 60 61 62 Varani S, Frascaroli G, Homman-Loudiyi M, Feld S, Landini MP, Soderberg-Naucler C. Human cytomegalovirus inhibits the migration of immature dendritic cells by down-regulating cell-surface CCRI and CCRS. J Leukoc Biol 2005;77:219-28. CrossRef, PubMed, CAS, Web of Science® Times Cited: 32 Reeves MB, Macry PA, Lehner PJ, Sissons JG, Sinclair JH. Latency, chromatin remodeling, and reactivation of human cytomegalovirus in the dendritic cells of healthy carriers. Proc Natl Acad Sci USA 2005;102:4140-5. CrossRef, PubMed, CAS, Web of Seience® Times 57, ADS Ronnblom L, Ramstedt U, Alm GV. Properties of human natural interferon-producing cells stimulated by tumor cell lines. Eur J Immunol 1983;13:471-6. Direct Link: © Abstract o PDF(675K) © References Siegal FP, Kadowaki N, Shodell M, Fitzgerald-Bocarsly PA, Shah K, Ho S, et al. The nature of the principal type 1 interferon-producing cells in human blood. Science 1999;284:1835~7. CrossRef, PubMed, CAS, Web of Science® Times Cited: 968 Bjorck P. Isolation and characterization of plasmacytoid dendritic cells from Flt3 ligand and granulocyte-macrophage colony-stimulating factor-treated mice. Blood 2001;98:3520-6. CrossRef, PubMed, CAS, Web of Science® Times Cited: 187 Kadowaki N, Antonenko S, Lau JY, Liu YJ. Natural interferon alpha/beta-producing cells link innate and adaptive immunity. J Exp Med 2000;192:219-26. CrossRef, PubMed, CAS, Web of Science® Times Ci 66 Cheeseman SH, Rubin RH, Stewart JA, Totkoff-Rubin NE, Cosimi AB, Cantell K, et al. Controlled clinical trial of prophylactic human-leukocyte interferon in renal transplantation. Effects on cytomegalovirus and herpes simplex virus infections. N Engl J Med 1979;300:1345- 9. CrossRef, PubMed, CAS, Web of Science® Times Cited: 314

    You might also like