DC-virus interplay: a double edged sword

Seminars in Immunology 16 (2004) 147–161

DC-virus interplay: a double edged sword Marie Larsson, Anne-Sophie Beignon, Nina Bhardwaj∗ NYU School of Medicine, 550 First Avenue, MSB507, New York, NY 10016, USA

Abstract Myeloid and plasmacytoid dendritic cells, a family of professional antigen presenting cells, are crucial in generating and maintaining anti-viral immunity. Many viruses have evolved to avoid, subvert, and even counterattack them. In this article, we focus on the tuning of innate and adaptive responses induced by human dendritic cells, and on the inhibition of their functions by viruses of medical significance. A constant “tug of war” goes on between dendritic cells and viruses and a main dendritic cell countermeasure is cross-presentation/priming. © 2004 Elsevier Ltd. All rights reserved. Keywords: Myeloid dendritic cells; Plasmacytoid dendritic cells; Virus; Immunity

1. A DC centric view of immunity Host defense against infection requires integrated responses between the innate and the adaptive arms of the immune system. The onset of the innate immune response is immediate and does not require prior exposure to pathogens, whereas effective adaptive immunity requires the orchestration of several sequential steps and the induction of strong memory cell-mediated responses. Nevertheless, the division between these two arms of the immune system is not absolute. Dendritic cells (DC) are appreciated for their pivotal role in linking innate and adaptive anti-viral immunity. The body is constantly exposed to a variety of infectious agents. The primary barriers against these pathogens are epithelial surfaces, for example, the skin and the mucosal linings of the gastrointestinal, respiratory and urogenital tracts where DCs are located. Penetration of these barriers Abbreviations: MDC, myeloid dendritic cell; pDC, plasmacytoid dendritic cell; LC, Langerhans cell; HPV, human papilloma virus; HSV-1, herpes simplex virus-1; HSV-2, herpes simplex virus-2; VZV, Varicella zoster virus; EBV, Epstein-Barr virus; CMV, cytomegalovirus; HHV-6, human herpes virus-6; DV, dengue virus; PIV, parainfluenza virus; MV, measles virus; RSV, respiratory syncytial virus; HIV, human immunodeficiency virus; TLR, Toll-like receptor; MHC, major histocompatibility complex; TCR, T cell receptor; APC, antigen presenting cell; IRF, interferon regulatory factor; IFN, interferon; IRAK, IL-1R-associated kinase; TNF, tumor necrosis factor; TRAF, TNFR-associated factor; F protein, fusion protein; HA protein, haemagglutinin protein; LPS, lipopolysaccharide; TRAIL, tumor necrosis factor-related apoptosis-inducing ligand; dsRNA, double strand RNA; BDCA, blood dendritic cell antigen; DC-SIGN, dendritic cell-specific intercellular adhesion molecule 3 grabbing nonintegrin; HSP, heat shock protein; ODN, oligodeoxynucleotide ∗ Corresponding author. Tel.: +1-212-263-5814; fax: +1-212-263-6729. E-mail address: [email protected] (N. Bhardwaj). 1044-5323/$ – see front matter © 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.smim.2004.02.002

leads to capture or detection of pathogens by DCs, their activation, and finally their migration to lymphoid organs where appropriate specific immune responses are initiated.

2. DC subtypes and location DCs are a heterogeneous population which differ in their (i) lineage, (ii) phenotype, including a differential, specialized and complementary expression of receptors for viral products, (iii) location, (iv) growth factor requirements, and (v) functions. Importantly, DCs can display plasticity or flexibility depending upon their sites or features of their local environment [1]. Myeloid DCs (MDC) are strategically located in peripheral tissues at the site of entry of most viruses. Langerhans cells (LC) are found in the epidermis and interstitial DCs in the dermis, mucosa and peripheral tissues [2]. Both can be derived from CD34+ hematopoietic progenitor cells. Two subsets of DC precursors circulate in the blood; the lineage negative CD11c+ MDC, and secondly, CD11c−, CD123+ (IL-3R alpha) plasmacytoid DCs (pDC) which are related to the lymphoid lineage [3]. pDC are not resident in healthy peripheral tissues but are found in lymphoid organs (thymus, bone marrow, spleen, tonsils and lymph nodes) [4–6] and are increased in inflamed tissues such as skin from patients suffering from Lupus erythematosus, allergen challenged mucosa or tumors [7,8]. pDC appear to be the principal interferon alpha-producing cells in the blood in their immature form, while MDC produce IL-12 [9]. Nevertheless, both DC subsets can induce antigen specific B and T cell responses [10,11]. The heterogeneity inherent to the DC populations confers the imprinting of differential

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immune responses to various pathogens which is amplified by cross-talk between the various subsets.

3. DC direct infection Viral infection is a multiphase process that includes virus uptake, genome replication, transcription and translation of viral gene products, assembly and production of virions. DCs express many of the molecules that are used by viruses to invade host cells. Among hijacked receptors, CD4, CCR5, CXCR4 expressed by pDC, blood MDC, and monocyte-derived MDC are used by HIV [12]. CD46, a complement receptor, expressed by virtually any nucleated cells is used by measles virus (MV) vaccine, whereas CD150 (SLAM) expressed by preactivated DC is used by wild type MV [13]. HSV-1 initially attaches to cell surface heparan sulfate proteoglycans and then binds to three specific surface receptors expressed differentially by DC according to their maturation state: HVEM (Hve-A) a member of TNF/NGF receptor family, Prr1 (Hve-C) and Prr2 (Hve-B), members of the Ig superfamily. Depending on the viruses, productive or abortive infection takes place in a DC (Table 1). High levels of viral replication can occur in the cases of HIV and MV within virus-induced syncytia [67,68]. Cytopathic effects of infection depend on the virus, the subset of DC and its maturation state. Apoptosis of infected cells, mostly immature MDCs, occurs for instance with HSV, vaccinia virus, influenza virus, and RSV and is an early mechanism to prevent viral replication and spread of virus. Interestingly, some viruses that induce death of infected MDC can trigger pDC survival (HSV, HIV, influenza virus) [63,69].

4. Detection of viruses and infected/inflamed microenvironment by DCs The first step in innate immunity is the recognition of viral components (non-self = stranger) via pattern recognition receptors (PRR) including Toll-like receptors (TLR) and sugar-binding C-lectin receptors (CLR), and of mediators produced by neighboring infected/dying cells (danger) like HSP [70], uric acid [71] or cytokines such as IFN type I [72]. 4.1. Via TLRs TLRs recognize constitutive and conserved microbial components (proteins, DNA or RNA) termed pathogenassociated molecular patterns (PAMP) as well as endogenous ligands which signal through TLR2 and TLR4 including HSP60, HSP70, gp96, beta-defensins and degradation products of extracellular matrix [73]. Ligands binding to these receptors initiate a cascade of intracellular signaling that leads to the activation of transcription factors including

NF-␬B, AP-1 and p38 [74,75] or induction of interferon regulatory factors (IRF) [76–79]. In DCs, TLR signaling triggers a maturation program, including the upregulation of the expression of HLA and co-stimulatory molecules and the secretion of cytokines such as TNF-␣, IL-6, IL-12 and IFN-␣. Blood MDC and pDC express a complementary set of TLR [80–83] (Fig. 1A) and therefore the subsets of TLR and DCs triggered shape the innate and adaptive responses [84,85]. TLR signaling specificities are based on differential coreceptors and/or adaptor molecules involved in the TLR-MyD88-IRAK-TRAF6 pathway. IRF3 nuclear translocation leads to IFN-␤ and IFN-␣4 secretion which signal via IFN␣/␤ receptor, induce IRF7 leading to the induction of IFN-␣ subtypes and activation of other anti-viral products in an autocrine–paracrine fashion [86,87]. IFN type I is secreted after triggering of TLR4, TLR3, TLR9 and TLR7, by their respective agonists: LPS, dsRNA, and synthetic poly I:C, unmethylated CpG-containing DNA and synthetic molecules of the imidazoquinoline family and guanosine derivatives. It is worth noting that the presence of dsRNA can lead to IFN type I secretion in a TLR3-independent way in MDC [88]. Furthermore, stimulation of TLR7 and TLR9 in pDCs induces the production of IFN type I in an IRF3 independent pathway [89,90] presumably because pDC express a high constitutive level of IRF7 [91]. The mechanisms of direct activation of IRF7 require further identification and might involve virus-dependent kinases [86]. Finally, signaling via the type I IFN pathway and not the release of type I IFN seems to participate in the maturation of DC [92–94]. Recent reports have described an involvement of TLR in viral detection and clearance. IRAK4 knockout mice are more susceptible to lymphocytic choriomeningitis virus (LCMV) infection than wild type animals [95]. TLR4 null mice also show impaired responses to RSV infection, although their responses to influenza virus infection are not defective [58,96,97]. TLR2 is responsible for the response to wild type MV HA protein and to CMV, whereas TLR4 mediates the response to RSV protein [98–100]. HSV-1 and HSV-2 DNA activate murine pDC to secrete IFN-␣ via TLR9 [101,102]. The genomes of some herpesviruses and vaccinia virus carry a relative abundance of CpG motifs compared to many other viruses, but so far the highest frequencies are found in bacteria [103]. The naturally occurring ligands of TLR7 and TLR8 are unknown, the hypothesis is that they sense products of the oxidative damage of nucleic acids from viruses and infected/dying cells [104]. TLR3, TLR7, TLR8 and TLR9 are expressed in endosomal compartments [105,106]. Infection itself can cause upregulation of TLR expression [107,108]. Finally, poxvirus A52R gene encodes a protein that can inhibit TLR signaling [109,110]. 4.2. Via CLRs CLRs are pathogen receptors with broad specificities. A range of CLRs are expressed by DCs and they primarily

Table 1 Interactions of some DNA viruses (A) and RNA viruses (B) with human dendritic cells Family

Virus

Disease

(A) Interactions of some DNA viruses with human dendritic cells Papovaviridae HPV Warts; some oncogenic viruses

Binding/entry receptors

Host tissue/cell

Interactions with human DC Subtypes

Replication Non permissive

KC only; non lytic in KC

LC

CAR; MHC class I;

Epithelial cells

MDC; pDC

Sensory neurons; epithelial cells; fibroblasts; keratinocytes; DC T cells; neurons

MDC; pDC

Low susceptibility (CAR− and ␣V␤3− ) of MDC; pDC? Productive in immature MDC; only IE and E genes are transcripts are generated in mature MDC; pDC? Productive infection in both immature and mature MDC; pDC? Non permissive Productive infection with endothelial-adapted strains in both immature and mature MDC; abortive infection with fibroblast-adapted strains; pDC? Productive

Depletion of LC from infected skin associated with viral-induced downregulation of E-cadherin by KC Recombinant virus to target DC under development

Adenoviridae

Adenovirus

Upper respiratory tract infection

Herpesviridae

HSV

Cold sores; genital herpes

HVEM (Hve-A); Prr-2 (Hve-B); Prr-1 (Hve-C); TLR9?

VZV

Varicella; herpes zoster

MR

EBV CMV

Oncogenic (lymphoma) No overt disease in immunocompetent hosts; complications in immunocompromised hosts

CD21 DC-SIGN; EGFR

Epithelial cells; B cells Epithelial cells; activated monocytes; DC

MDC Monocyte-derived MDC; LC; pDC

HHV-6

Roseola; oncogenic

CD46

Monocyte-derived MDC

Vaccinia virus

Vaccination against smallpox (by scarification)

Heparan sulfate; chondroitin sulfate

T cells; B cells; NK cells; monocytes; macrophages Epithelial cells

Monocyte-derived MDC

Immature > mature; abortive in both immature and mature

Apoptosis; immature > mature

DC-SIGN

Brain; skin; LN

Productive in MDC; pDC?

Apoptosis

Sialic acid

Epithelial cells

Productive in MDC; productive in pDC

Apoptosis; survival

CD46; CD150; TLR2 Calveolae; surface glycoproteins; TLR4-CD14 DC-SIGN, L-SIGN

Epithelial cells Epithelial cells

Monocyte-derived MDC; LC; pDC Monocyte-derived MDC; blood MDC; pDC Monocyte-derived MDC Monocyte-derived MDC Monocyte-derived MDC

Productive Productive Productive; mature > immature

Apoptosis Apoptosis Apoptosis; immature > mature

Poxviridae

(B) Interactions of RNA viruses with human dendritic cells Flaviviridae DV DF; DHF Orthomyxoviridae

Influenza virus

Flu

Paramyxoviridae

PIV MV RSV

Bronchiolitis, pneumonia Measles Bronchiolitis, pneumonia

Filiviridae

Ebola virus

EHF

Retroviridae

HIV

AIDS

␣Mb2, ␣V␤3, ␣V␤5

CD4; CCR5, CXCR4; DC-SIGN, langerin

Macrophages; liver; LN, spleen; DC CD4 T cells

Monocyte-derived MDC; pDC

Other

Apoptosis of MDC; survival of pDC

No apoptosis

Apoptosis

[14,15]

[16,17]

[18–25]

Transfer to T cells

[26,27]

Apoptosis of monocytes Latent (no replication) in a DC/myeloid lineage precursors; inhibition of monocytes differentiation into MDC

[28] [29–34]

Transfer to T cells

[35,36]

[37,38]

pDC involved in pathology (DF to DHF)

[39–45] [46–48]

Monocyte survivals Syncytia

[49] [50–55] [56–58]

Monocyte derived-MDC

Productive in MDC

Transfer to host cells?

[59–62]

Monocyte derived-MDC; MDC; pDC

Non productive in MDC; productive in pDC

Transfer to T cells; syncytia of MDC and T cells

[63–66]

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?

References Cell death

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Fig. 1. Differential expression of Toll like receptors (A) and C-type lectin receptors (B) by human plasmacytoid dendritic cells and myeloid dendritic cells.

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bind carbohydrate containing structures on microbes. DC-SIGN (CD209) is found on interstitial DC, langerin (CD207) on LC and mannose R (CD206) on dermal DC and blood MDC. Immature MDC express higher levels of CLR than mature MDC [111]. pDC do not express DC-SIGN but other lectins including BDCA-2 and BDCA-4 [112] (Fig. 1B). DC-SIGN binding is required for infection of DC by CMV and DV [29,41], whereas some viruses including Ebola virus, HCV and HIV can target DC-SIGN for trans-infection [59,111,113]. In the cases of mature MDC and pDC, HIV-1 binding to CD4 predominates. DC-SIGN triggering usually does not result in upregulation of costimulatory molecules contrary to TLR triggering. In fact its role in antigen processing and presentation of viral antigens remains to be fully elucidated. Anti-BDCA-2 Ab inhibits the production of IFN type I by pDC and PBMC in response to influenza virus and HSV [114,115] although pDC viability and maturation are not affected. The role of BDCA-2 in the binding/detection of viruses remains to be determined.

5. Effector components of the innate anti-viral immunity

151

type I exert. For instance HPV infection of keratinocytes prevents activation of IFN-␣ inducible genes and its subsequent secretion and hence does not arouse “suspicion” from neighboring LC. In human monocyte-derived MDC, influenza virus encodes nonstructural protein 1 which sequesters dsRNA explaining the low ability of infected MDC to produce IFN type I [88]. 5.2. Recruitment of innate effector cells at the site of infection The migration of MDC precursors to the site of infection in peripheral tissues may be regulated by MCP binding to CCR2 as well as CCL20 (MIP-3a) and ␤-defensins interacting with CCR6 [124–126]. Neutrophils, monocytes and NK cells access sites of infection in response to proinflammatory chemokines secreted by activated DCs including CXCL8 (IL-8), CXCL10 (IP-10), CCL3 (MIP-1a), CCL4 (MIP-1b) and CCL5 (RANTES) [127]. Poxviruses and herpes viruses dampen the immune response by secreting homologues of chemokine receptors that act as antagonists and prevent attraction of DCs to the site of infection [38,128]. 5.3. Activation of NK and NKT cells

5.1. IFN type I-mediated anti-viral defense Many, if not all, nucleated cells can produce IFN type I and respond to it by inducing an anti-viral state. IFN type I has pleiotropic effects including inhibition of viral replication, activation of NK cells and macrophages, enhancement of MHC class I molecules expression, TH1 polarization, differentiation of DC and the promotion of crosspriming [116]. Binding of IFN type I to IFN␣/␤R activates the JAK/STAT pathway. It results in the transcription of genes encoding proteins with anti-viral activity, such as Mx proteins (GTPases), which target viral nucleocapsids and inhibit RNA synthesis, 2 ,5 -oligoadenylate synthetase (OAS) and RNase L nuclease which mediate RNA degradation, RNA-dependent protein kinase PKR which inhibits translation initiation, or pro-apoptotic p53 [117,118]. PKR activation occur after stimulation of TLR4 or TLR9 in murine macrophages and Mx and OAS after in vivo treatment with TLR7 or TLR8 ligands [119–121]. pDC are the most powerful IFN type I producing cells. However, viral infection can also switch MDC into IFN producing cells in mice and humans [88]. Infection of monocyte-derived MDC with DV, RSV, HSV-1, PIV3, MV or influenza virus leads to low levels of IFN type I secretion. Furthermore, influenza virus infection results in MxA expression, which inhibits the primary viral transcription [46,48]. Viruses can inhibit the IFN type I innate defense at different levels [122,123]. By inhibiting IFN type I secretion, the virus affects both the infected cell and neighboring non-infected cells, due to the autocrine-paracrine effects IFN

NK cells are a crucial component of the anti-viral innate immune responses as a result of their early production of cytokines, chemokines and ability to lyse target cells without prior sensitization. It remains to be determined whether NKT cells are involved in anti-viral immunity by acting as direct cytotoxic effector cells or through the modulation of adaptive immunity [129–131]. Complete clearance of intracellular viruses depends on the destruction of infected cells by NK cells and CTLs via release of cytotoxic granules, binding to apoptosis-inducing receptors, as well as anti-viral cytokines such as IFN-␥ and TNF-␣. NK receptors can positively regulate NK cell-mediated cytotoxicity and cytokine production, for example, NKp46 directly recognizes viral products, such as HA from influenza virus and HA/NA from Parainfluenza virus. Other NK receptors negatively regulate cell-mediated cytotoxicity by recognizing MHC class I molecules. The dominant ligands for NK cells inhibitory receptors are HLA-C and HLA-E [132–134]. For example, infection of MDC with influenza virus is associated with a reduced susceptibility to lysis by NK cells because of the upregulation of MHC I molecules [135]. Recently, reports have emphasized a critical role of mature MDC in the mobilization and activation of NK cells via chemokine-mediated recruitment, cytokine mediatedactivation and contact-dependent activation [136–142]. Activated NK cells can prime DCs to induce protective CD8+ T cell responses and down modulate ongoing immune responses by directly lysing immature DCs [143,144]. In the context of viral infection, escape from NK cell recognition may occur through the expression of virally encoded MHC

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class I molecule homologues, the relative or selective upregulation of HLA-C and HLA-E, the production of virally encoded cytokines, or the induction of cytokine production by DCs that impair NK cell activation, mainly IL-10 [145]. 5.4. pDC pDC can produce higher levels of IFN type I than other cell types and are thus responsible for the systemic IFN type I responses to enveloped viruses including HIV, influenza virus, HSV, Sendai virus, MV, mumps virus, Newcastle disease virus, vesicular stomatitis virus and CMV [10,22,23,146,147]. Furthermore, the profile of IFN genes expressed in virus-stimulated pDC, monocytes and monocyte-derived MDC demonstrates that the range of the subtypes of IFN-␣ expressed in pDC is broader [91]. The ability of pDC to produce IFN type I is decreased after maturation (IL-3, CD40L) and by IL-10 treatment [148–150]. IFN type I not only reduces viral replication [146], but also acts as a survival factor for pDC [22]. In vivo, HIV infection is associated with a decline in blood pDC frequency and this is inversely correlated with

susceptibility to opportunistic infections. Long-term survivors have a higher frequency of blood pDC compared to healthy individuals [151]. The CpG induced IFN type I secretion by pDC is also lower in the cases of dengue fever, dengue hemorrhagic fever and non DV-related febrile syndromes as compared to healthy donors [39].

6. Adaptive immune response against viral infection DCs are essential to the initiation of the adaptive immune response, which involve the activation of distinctive effector cells, for example, B cells, CD4+ helper cells and CD8+ cytolytic T cells, capable of specific recognition of microbial antigens. DCs play a key role in determining the final outcome of the response through production of different cytokines and chemokines depending on the degree of maturation, and inflammatory signals received when interacting with viruses [152]. T cell immune responses are initiated in the T cell areas of secondary lymphoid organs where na¨ıve T cells encounter DCs presenting antigens taken up in peripheral

Fig. 2. Possible scenarios for induction of adaptive immune responses by human dendritic cells during viral infections.

M. Larsson et al. / Seminars in Immunology 16 (2004) 147–161

tissues or locally. DC acquisition and presentation of viral antigens occurs via direct infection or uptake of exogenous sources of viral antigens by DCs in the tissues, for example, virus-infected apoptotic or necrotic cells. Chemokines play a central role in guiding DCs and lymphocytes into secondary lymphoid organs and their homing to T cell and B cell zones therein, CCR7 and CXCR5, respectively [153] (Fig. 2). 6.1. Viral effects on DC maturation Viruses can induce maturation in DCs by direct infection, viral interaction, or as a bystander effect of the infection. Most RNA viruses (DV, RSV, PIV3, MV, influenza virus) [13,45,46,48,49,57,154] infect and induce maturation in MDCs. Dengue and influenza virus infection induce bystander maturation besides direct maturation of infected MDCs. In contrast, HIV does not mature MDCs, but does activate pDCs [63,146]. RNA viruses activate the signaling pathway/s for maturation through dsRNA intermediates which activate the NF-␬B pathway through PKR-dependent or -independent pathways [88]. Infection with the DNA viruses CMV and vaccinia induce a block of maturation [34,37] in the infected MDCs whereas HHV6 induces maturation [36]. HSV inhibits the maturation of MDC while it induces maturation of pDC [20,155] (Table 2). 6.1.1. Direct and bystander maturation effects on DCs by virus infection 6.1.1.1. Influenza A virus. Influenza infection induces maturation of immature monocyte-derived MDCs and blood DCs [10,46–48]. These cells also down regulate CXCR3 and L-selectin, and upregulate CCR7 which should mediate their migration and homing into the lymph node. Furthermore, influenza A virus infection induces production of IL-12 [46,47]. The mechanism of maturation however remains undetermined. One possibility is IFN-␣, which activates PKR, an activator of gene transcription via the NF-␬B pathway. 6.1.1.2. Measles virus. Initially MV interaction/infection activates the maturation program in MDCs via the NF-␬B pathway [166]. This may occur via the hemaglutinin protein (H) on wild type virus, both to infect MDCs and to activate them via TLR2 [51]. Infection with MV abrogates the production of IL-12 by CD40 matured MDCs [54] whereas IL-12 production is sustained after exposure to LPS or SAC [54]. Thus, it seems that the virus adversely intersects the CD40 maturation/signaling pathway in MDCs. It is not clear whether these different effects relate to DC maturation state or source, MV strain, or receptor used for virus entry. 6.1.1.3. HIV-1. HIV-1 infects selected populations of DCs, in particular immature MDCs and LCs. In vitro, HIV exposure or infection does not induce maturation of MDCs, nor does it inhibit their maturation [63]. In vivo, circulating

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blood pDCs and CD11c+ MDCs from HIV+ individuals are infected by HIV-1 and are more mature compared to their counterparts in healthy individuals [65]. HAART suppression of viral load leads to increase in blood DC numbers and a return to an immature phenotype [167]. In vitro, pDCs matured by direct HIV exposure release TNF-␣ and IFN-␣ which induce the bystander maturation of MDCs. Thus in untreated HIV infection, the drop in blood DC number may not only reflect cell death due to infection but also migration to lymph nodes as a result of maturation-induced upregulation of CCR7 (Fonteneau et al., Blood, in press). 6.1.2. Viral driven inhibition of DC maturation 6.1.2.1. HSV-1. Infection of immature MDCs with HSV-1 inhibits maturation in response to LPS as they fail to upregulate CD83, costimulatory molecules, CCR7 or synthesize IL-12, TNF-␣, IL-6 and IL-10 [20]. More interestingly, infection induces the bystander maturation of uninfected cells, probably due to the transeffects of virally induced proteins [20]. Mature MDCs are more resistant to HSV-1 and have unchanged MHC class I expression and ELC (CCL19; ligand to CCR7) responsiveness but infected mature MDC exert inhibitory T cell stimulatory capacity [168]. Infection of mature MDCs with HSV-1 also leads to specific degradation of CD83 [168]. Altogether, these data suggest that HSV-1 infected DCs are compromised with respect to function, and that any induced T cell immunity will depend upon bystander activation of MDCs which have exogenously acquired HSV antigens or via pDCs undergoing maturation after HSV exposure. 6.1.2.2. Vaccinia virus. Vaccinia virus infects both immature and mature MDCs [37,162]. Infection of immature MDCs leads to a block in their maturation with inhibition in their expression of CD83, CD86, HLA DR and CD25. The production of cytokine receptor homologues may inhibit maturation effects mediated by TNF-␣ or IFN-␣ [38]. Moreover, Vaccinia virus may block TLR intracellular signaling pathways involved in maturation [110]. 6.1.2.3. CMV. MDCs and LCs can be infected with CMV strains grown in endothelial cells and fibroblasts, but only the former supports productive infection [30,33,34]. CMV impairs MDC maturation, and downregulates costimulatory and adhesion molecules in both immature and mature MDCs [34]. Another study has only found a reduction in MHC class I and II molecules following CMV infection of mature MDCs [31]. Altogether these data support recent evidence that CMV immunity is achieved mainly by DC cross presentation. 6.2. Viral effects on T cell activation by infected MDCs By suppressing DC maturation and migration capacity, many viruses can persist in the host. The expression of gene

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products that directly alter the immune response (e.g., cytokines and cytokine receptor homologues), interfere with MHC class I and II presentation via inhibitors of TAP [169] and skew T cell responses through altered cytokine production are other mechanisms used by viruses to evade adaptive immunity [128,170,171] (Table 2). 6.2.1. TH2 skewing of anti-viral immune responses activated by DCs DC activation by virus or its components induces the production of cytokines which may promote the development of either TH1 or TH2. The pDC is a major producer of type I IFNs and can induce a TH1 T cell response, for example, after influenza virus infection [10,47]. MDCs produce IL-12 when infected with influenza A virus [46], but many viruses decrease or inhibit IL-12 production (DV [40,43], MV [52], HHV6 [36]). In the case of MV, the inhibition of IL-12 and induction of IL-4 and IL-10 by MDCs may account for the TH2 skewing of the CD4+ T cell response [52]. Interestingly, RSV induces predominantly TH2 responses even if infected MDCs can produce some IL-12, probably due to the production of IL-11 and PGE2 [56]. 6.2.2. Viral blunting of T cell responses Viral proteins expressed on the MDC surface are another mechanism used by viruses to blunt or block T cell activation. This strategy is used to avoid activation of T cells during MV infection in vivo or when MV infected MDCs fail to adequately stimulate either mitogenic or allogeneic T cell responses in vitro [13]. The MDC induced suppression of T cell proliferation in vitro requires cell–cell contact and involves the viral glycoproteins H and F expressed by the MDCs late in infection [172]. Virus induced expression of regulatory proteins on MDCs is also used to avoid immune activation or recognition. MV infected MDCs induce apoptosis of T cells due to MV induced TRAIL expression [173]. Similarly, CMV infection induces CD95L and TRAIL expression on mature MDCs which blunt anti-viral T cell responses via induction of apoptosis [31]. The ability of both CD11c+ blood MDC and pDC from HIV infected individuals to stimulate allogeneic T cells is impaired. This impairment is not due to secondary infection of T cells [65] but possibly due to expression of HIV protein such as gp120, shown to induce apoptosis in T cells [63]. 6.3. DC presentation of viral-derived antigens and subsequent activation of T cells CD8+ T cells are critical components of the immune response to fight virus infection. The development of antigen specific CTLs requires presentation of antigenic peptides by MHC class I molecules on DCs and helper function provided by CD4+ T cells. CTLs, via their T cell receptors (TCRs), recognize major histocompatibility complex (MHC) class I molecules bearing antigenic peptides of 8–10

amino acids. Peptides that bind to MHC class I molecules are derived from endogenously synthesized proteins, either the cell’s own proteins or proteins synthesized within the cell’s cytoplasm by infectious agents. This is referred to as the “endogenous” pathway of antigen presentation. In contrast to CD8+ T cells, CD4+ T cells recognize MHC class II molecules expressing antigenic peptides derived from the “exogenous” pathway [174]. CTLs are essential for elimination of virus infected cells so it not surprising that viruses have evolved ways to avoid or interfere with their activation. DCs have developed specialized pathways to present viral antigens on MHC class I molecules through an exogenous pathway, referred to as cross presentation. Cross presentation has increasingly become recognized to be necessary, if not essential, for a wide variety of CD8+ T cell-mediated immune responses, including those to viruses, bacteria, allografts, tumor and self-antigens [175] (Table 2). 6.3.1. Viral crosspresentation by DCs Antigens can be acquired from exogenous cell-associated sources by professional APCs to be presented on MHC class I molecules, this phenomenon was termed “crosspriming” [176–182]. The cells responsible for the in vivo crosspresentation in mice were DCs expressing CD11c, CD8 alpha, DEC-205 and low levels of CD11b [183,184]. MDCs can acquire exogenous viral antigens via different sources, many originating from dying infected cells, such as, virus infected apoptotic cells and necrotic cells [163,185], HSPs and immune complexes. This presentation can lead to protective immunity only if danger signals are simultaneously provided, for example, inflammatory cytokines in the milieu [177], as in their absence the out come will be tolerance [177,184]. Substantial evidence exists that crosspresentation of cell-associated antigen and particulate antigens is more efficient than presentation of soluble antigens, up to 105 -fold in some cases [186–188]. Crosspresentation by MDCs of exogenous antigen derived from infected cells has now been confirmed in vitro for a variety of viruses: influenza virus, HIV-1, Vaccinia virus, Canarypox virus, EBV and CMV which activate both CD8+ T cells, and in some cases CD4+ T cell responses [157,158,163,185,189–192]. For viruses that do not infect MDCs such as EBV or viruses that severely impair their APC function such as HSV-1, crosspresentation may be the only/main mechanism to achieve protective immunity. EBV does not infect DCs but strong anti-viral immunity is still developed in infected individuals. EBV infected B cells may be the source of viral antigen for MDC crosspresentation and induction of immunity in vivo. In vitro studies have shown that EBV transformed B cell lines can serve as a source of antigens for MDCs to activate memory CD4+ and/or CD8+ T cells specific for EBNA-1, EBNA-3A and latent membrane protein 2 [157,158] and to prime EBV specific CD8+ and CD4+ T cells from EBV negative donors [192]. Crosspriming allows induction of CTLs even when APC function is compromised.

Table 2 Viral effects on dendritic cell maturation and cytokine/chemokine production and T cell responses Effect on MDCs

Maturation of pDCs

HHV-6

Maturation

Vaccinia virus DV

Inhibit maturation of IDC Maturation of infected DC bystander maturation uninfected Maturation MDC, CD11c+ blood DCs Maturation

Influenza virus PIV-3 MV RSV Ebola virus HIV

Maturation

T helper cell type

T cell response

Immunity via

References

No cytokines, no IL-12 (pDCs: IFN-␣, TNF-␣)

Decrease MHC class I

Decreased TH1

Impaired T cell stimulation

Cross presentation? Cross presentation?

[14,15] [18–21,156]

Impaired T cell stimulation

Cross presentation?

[26,27]

Cross presentation Cross presentation

[157,158] [30,31,159–161]

Cross presentation?

[36]

Cross presentation Cross presentation?

[37,162–164] [39,40,43–45]

[46–48]

Impairment in T cell responses

Direct infection/Cross presentation Cross presentation?

[49]

Impairment in T cell activation

Cross presentation

[50–55]

Direct infection?/cross presentation? Cross presentation? Cross presentation/direct infection

[56,57]

Decrease in MHC class I and II

Decrease in MHC class I RANTES, MIP-1b, TNF-␣, no IL-12 TNF-␣ TNF-␣, IFN-␣, no IL-6, low or no IL-12, no IL-10 IL-12, no IL-10 or IL-11 TNF-␣, IFN-␣, no IL-6, IL-12, no IL-10 IFN-␣, IL-6, IL-1b, IL-4, no IL-12 IL-12, IL-6, IL-11, PGE2 , low IL-10, IL-4?

Maturation, expect CD40 maturation Induce maturation No effect on immature MDCs No effect on monocyte derived MDCs and CD11c+ MDCs

MHC class I/II

Maturation

(pDCs: IFN-␣, TNF-␣)

Impaired T cell stimulation

Apoptosis of high affinity T cells ACCD Increased MHC class I

TH1 response

TH2 response

Functional T cell activation

Predominant TH2 response Down regulation MHC class I (nef)

TH2 response (late stages AIDS)

Impaired T cell activation Dysfunctional CD8 T cells

M. Larsson et al. / Seminars in Immunology 16 (2004) 147–161

Possible viral effects on DC APC function and T cell activation HPV No infection? N/D HSV-1 Inhibit maturation of Maturation immature MDCs bystander maturation of uninfected MDCs VZV No maturation of immature D/D MDCs; Mature DC down regulate,CD83, CD80, CD86 EBV No infection CMV Inhibition of maturation

Cytokines/chemokines

[61,165] [63–66]

155

156

M. Larsson et al. / Seminars in Immunology 16 (2004) 147–161

There is so far no evidence of crosspresentation by pDCs in the human system. However, pDC might be involved indirectly by promoting cross-presentation by MDC via IFN type I.

7. Conclusion Immunity against many viruses is now achieved by vaccination as the viral infection itself can have a lethal outcome, as in MV infection. Vaccination against smallpox using Vaccinia virus resulted in the eradication of this disease. Viral vaccine candidates against viral infections include live attenuated viruses, inactivated viruses, and recombinant viral vectors (e.g., poxvirus, adenovirus, alphavirus) [193–195]. The combination of recombinant viral vectors with DNA-based strategies [196] has heightened efficacy and indirect targeting to DCs may contribute to the immunogenicity seen. The efficacy of alphavirus vectors may be explained by their capacity to actively target DCs in vivo [197,198], thus directly loading them with antigens for presentation to the immune system. However, given the adverse effects viruses impart to the immune system at multiple levels, the choice of vaccine vectors must take into account not only how to effectively target DCs in vivo but simultaneously how to maintain effective APC function. Future strategies will need to consider how to manipulate viral vectors to maximize the induction of immunity, for example, via elimination of inhibitory viral products especially those which might compromise DC function and addition of factors which promote immune responses, for example, TH1 skewing cytokines such as IL-12, TLRs targeting to heighten immunity, cytokines to promote DC maturation and chemokines to attract other DCs into the milieu. The need to develop non-replicating vectors which are engineered in such ways may avoid the concerns of reversal of attenuation in diseases such as HIV-1 infection. Further understanding of DC-virus interplay, in particular of DC subsets and virus receptors will enable the construction of suitable vaccine vectors which no longer evade the onset of immune responses at least at the DC level.

Acknowledgements These studies were supported by grants to M. Larsson (FAIR award, NYU CFAR award) and to N. Bhardwaj (AI 44628, a Burroughs Wellcome Clinical Investigator Award, a Doris Duke Distinguished Clinical Scientist Award). N. Bhardwaj is an Elizabeth Glaser Scientist.

References [1] Liu YJ, Kanzler H, Soumelis V, Gilliet M. Dendritic cell lineage, plasticity and cross-regulation. Nat Immunol 2001;2(7):585–9.

[2] Steinman RM. Dendritic cells and the control of immunity: enhancing the efficiency of antigen presentation. Mt Sinai J Med 2000;68:160–6. [3] Briere F, Bendriss-Vermare N, Delale T, et al. Origin and filiation of human plasmacytoid dendritic cells. Hum Immunol 2002;63(12):1081–93. [4] Fong L, Mengozzi M, Abbey NW, Herndier BG, Engleman EG. Productive infection of plasmacytoid dendritic cells with human immunodeficiency virus type 1 is triggered by CD40 ligation. J Virol 2002;76(21):11033–41. [5] Bendriss-Vermare N, Barthelemy C, Durand I, et al. Human thymus contains IFN-alpha-producing CD11c(−) myeloid CD11c(+), and mature interdigitating dendritic cells. J Clin Investig 2001;107(7):835–44. [6] Vandenabeele S, Hochrein H, Mavaddat N, Winkel K, Shortman K. Human thymus contains 2 distinct dendritic cell populations. Blood 2001;97(6):1733–41. [7] Farkas L, Beiske K, Lund-Johansen F, Brandtzaeg P, Jahnsen FL. Plasmacytoid dendritic cells (natural interferon–alpha/betaproducing cells) accumulate in cutaneous lupus erythematosus lesions. Am J Pathol 2001;159(1):237–43. [8] Jahnsen FL, Lund-Johansen F, Dunne JF, Farkas L, Haye R, Brandtzaeg P. Experimentally induced recruitment of plasmacytoid (CD123high) dendritic cells in human nasal allergy. J Immunol 2000;165(7):4062–8. [9] Banchereau J, Pulendran B, Steinman R, Palucka K. Will the making of plasmacytoid dendritic cells in vitro help unravel their mysteries? J Exp Med 2000;192(12):F39–44. [10] Fonteneau JF, Gilliet M, Larsson M, et al. Activation of influenza virus-specific CD4+ and CD8+ T cells: a new role for plasmacytoid dendritic cells in adaptive immunity. Blood 2003;101(9):3520– 6. [11] Jego G, Palucka AK, Blanck JP, Chalouni C, Pascual V, Banchereau J. Plasmacytoid dendritic cells induce plasma cell differentiation through type I interferon and interleukin 6. Immunity 2003;19(2):225–34. [12] Turville SG, Cameron PU, Handley A, et al. Diversity of receptors binding HIV on dendritic cell subsets [comment]. Nat Immunol 2002;3(10):975–83. [13] Schneider-Schaulies S, Klagge IM, ter Meulen V, et al. Dendritic cells and measles virus infection. Curr Top Microbiol Immunol 2003;276:77–101. [14] Matthews K, Leong CM, Baxter L, et al. Depletion of Langerhans cells in human papillomavirus type 16-infected skin is associated with E6-mediated down regulation of E-cadherin. J Virol 2003;77(15):8378–85. [15] Tindle RW. Immune evasion in human papillomavirus-associated cervical cancer. Nat Rev Cancer 2002;2(1):59–65. [16] Zou W, Borvak J, Wei S, Isaeva T, Curiel DT, Curiel TJ. Reciprocal regulation of plasmacytoid dendritic cells and monocytes during viral infection. Eur J Immunol 2001;31(12):3833–9. [17] Rea D, Schagen FH, Hoeben RC, et al. Adenoviruses activate human dendritic cells without polarization toward a T-helper type 1-inducing subset. J Virol 1999;73(12):10245–53. [18] Mikloska Z, Bosnjak L, Cunningham AL. Immature monocytederived dendritic cells are productively infected with herpes simplex virus type 1. J Virol 2001;75(13):5958–64. [19] Kruse M, Rosorius O, Kratzer F, et al. Mature dendritic cells infected with herpes simplex virus type 1 exhibit inhibited T-cell stimulatory capacity. J Virol 2000;74(15):7127–36. [20] Salio M, Cella M, Suter M, Lanzavecchia A. Inhibition of dendritic cell maturation by herpes simplex virus. Eur J Immunol 1999;29(10):3245–53. [21] Pollara G, Speidel K, Samady L, et al. Herpes simplex virus infection of dendritic cells: balance among activation, inhibition, and immunity. J Infect Dis 2003;187(2):165–78.

M. Larsson et al. / Seminars in Immunology 16 (2004) 147–161 [22] Kadowaki N, Antonenko S, Lau JY, Liu YJ. Natural interferon alpha/beta-producing cells link innate and adaptive immunity. J Exp Med 2000;192(2):219–26. [23] Siegal FP, Kadowaki N, Shodell M, et al. The nature of the principal type 1 interferon-producing cells in human blood. Science 1999;284(5421):1835–7. [24] Milone MC, Fitzgerald-Bocarsly P. The mannose receptor mediates induction of IFN-alpha in peripheral blood dendritic cells by enveloped RNA and DNA viruses. J Immunol 1998;161(5):2391–9. [25] Ankel H, Westra DF, Welling-Wester S, Lebon P. Induction of interferon-alpha by glycoprotein D of herpes simplex virus: a possible role of chemokine receptors. Virology 1998;251(2):317–26. [26] Abendroth A, Morrow G, Cunningham AL, Slobedman B. Varicellazoster virus infection of human dendritic cells and transmission to T cells: implications for virus dissemination in the host. J Virol 2001;75(13):6183–92. [27] Morrow G, Slobedman B, Cunningham AL, Abendroth A. Varicellazoster virus productively infects mature dendritic cells and alters their immune function. J Virol 2003;77(8):4950–9. [28] Li L, Liu D, Hutt-Fletcher L, Morgan A, Masucci MG, Levitsky V. Epstein-Barr virus inhibits the development of dendritic cells by promoting apoptosis of their monocyte precursors in the presence of granulocyte macrophage-colony-stimulating factor and interleukin4. Blood 2002;99(10):3725–34. [29] Halary F, Amara A, Lortat-Jacob H, et al. Human cytomegalovirus binding to DC-SIGN is required for dendritic cell infection and target cell trans-infection. Immunity 2002;17(5):653–64. [30] 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. Eur J Immunol 2003;33(6):1528–38. [31] Raftery MJ, Schwab M, Eibert SM, Samstag Y, Walczak H, Schonrich G. Targeting the function of mature dendritic cells by human cytomegalovirus: a multilayered viral defense strategy. Immunity 2001;15(6):997–1009. [32] Hahn G, Jores R, Mocarski ES. Cytomegalovirus remains latent in a common precursor of dendritic and myeloid cells. Proc Natl Acad Sci USA 1998;95(7):3937–42. [33] Riegler S, Hebart H, Einsele H, Brossart P, Jahn G, Sinzger C. Monocyte-derived dendritic cells are permissive to the complete replicative cycle of human cytomegalovirus. J Gen Virol 2000;81(Pt 2):393–9. [34] 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(13):7563–74. [35] Asada H, Klaus-Kovtun V, Golding H, Katz SI, Blauvelt A. Human herpesvirus 6 infects dendritic cells and suppresses human immunodeficiency virus type 1 replication in coinfected cultures. J Virol 1999;73(5):4019–28. [36] Kakimoto M, Hasegawa A, Fujita S, Yasukawa M. Phenotypic and functional alterations of dendritic cells induced by human herpesvirus 6 infection. J Virol 2002;76(20):10338–45. [37] Engelmayer J, Larsson M, Subklewe M, et al. Vaccinia virus inhibits the maturation of human dendritic cells: a novel mechanism of immune evasion. J Immunol 1999;163(12):6762–8. [38] Seet BT, Johnston JB, Brunetti CR, et al. Poxviruses and immune evasion. Annu Rev Immunol 2003;21:377–423. [39] Pichyangkul S, Endy TP, Kalayanarooj S, et al. A blunted blood plasmacytoid dendritic cell response to an acute systemic viral infection is associated with increased disease severity. J Immunol 2003;171(10):5571–8. [40] Libraty DH, Pichyangkul S, Ajariyakhajorn C, Endy TP, Ennis FA. Human dendritic cells are activated by dengue virus infection: enhancement by gamma interferon and implications for disease pathogenesis. J Virol 2001;75(8):3501–8.

157

[41] Tassaneetrithep B, Burgess TH, Granelli-Piperno A, et al. DC-SIGN (CD209) mediates dengue virus infection of human dendritic cells. J Exp Med 2003;197(7):823–9. [42] Navarro-Sanchez E, Altmeyer R, Amara A, et al. Dendritic-cellspecific ICAM3-grabbing non-integrin is essential for the productive infection of human dendritic cells by mosquito-cell-derived dengue viruses. EMBO Rep 2003;4(7):723–8. [43] Marovich M, Grouard-Vogel G, Louder M, et al. Human dendritic cells as targets of dengue virus infection. J Investig Dermatol Symp Proc 2001;6(3):219–24. [44] Wu SJ, Grouard-Vogel G, Sun W, et al. Human skin Langerhans cells are targets of dengue virus infection. Nat Med 2000;6(7):816– 20. [45] Ho LJ, Wang JJ, Shaio MF, et al. Infection of human dendritic cells by dengue virus causes cell maturation and cytokine production. J Immunol 2001;166(3):1499–506. [46] Cella M, Salio M, Sakakibara Y, Langen H, Julkunen I, Lanzavecchia A. Maturation, activation, and protection of dendritic cells induced by double-stranded RNA. J Exp Med 1999;189(5):821–9. [47] Cella M, Facchetti F, Lanzavecchia A, Colonna M. Plasmacytoid dendritic cells activated by influenza virus and CD40L drive a potent TH1 polarization. Nat Immunol 2000;1(4):305–10. [48] Larsson M, Messmer D, Somersan S, et al. Requirment of mature dendritic cells for efficient activation of influenza A-specific memory CD8+ T cells. J Immunol 2000;165:1182–90. [49] Plotnicky-Gilquin H, Cyblat D, Aubry JP, et al. Differential effects of parainfluenza virus type 3 on human monocytes and dendritic cells. Virology 2001;285(1):82–90. [50] Schneider-Schaulies S, ter Meulen V. Triggering of and interference with immune activation: interactions of measles virus with monocytes and dendritic cells. Viral Immunol 2002;15(3):417–28. [51] Bieback K, Lien E, Klagge IM, et al. Hemagglutinin protein of wild-type measles virus activates toll-like receptor 2 signaling. J Virol 2002;76(17):8729–36. [52] Servet-Delprat C, Vidalain PO, Bausinger H, et al. Measles virus induces abnormal differentiation of CD40 ligand-activated human dendritic cells. J Immunol 2000;164(4):1753–60. [53] Murabayashi N, Kurita-Taniguchi M, Ayata M, Matsumoto M, Ogura H, Seya T. Susceptibility of human dendritic cells (DCs) to measles virus (MV) depends on their activation stages in conjunction with the level of CDw150: role of Toll stimulators in DC maturation and MV amplification. Microb Infect 2002;4(8):785–94. [54] Fugier-Vivier I, Servet-Delprat C, Rivailler P, Rissoan MC, Liu YJ, Rabourdin-Combe C. Measles virus suppresses cell-mediated immunity by interfering with the survival and functions of dendritic and T cells. J Exp Med 1997;186(6):813–23. [55] Grosjean I, Caux C, Bella C, et al. Measles virus infects human dendritic cells and blocks their allostimulatory properties for CD4+ T cells. J Exp Med 1997;186(6):801–12. [56] Bartz H, Buning-Pfaue F, Turkel O, Schauer U. Respiratory syncytial virus induces prostaglandin E2, IL-10 and IL-11 generation in antigen presenting cells. Clin Exp Immunol 2002;129(3):438–45. [57] Bartz H, Turkel O, Hoffjan S, Rothoeft T, Gonschorek A, Schauer U. Respiratory syncytial virus decreases the capacity of myeloid dendritic cells to induce interferon-gamma in naive T cells. Immunology 2003;109(1):49–57. [58] Kurt-Jones EA, Popova L, Kwinn L, et al. Pattern recognition receptors TLR4 and CD14 mediate response to respiratory syncytial virus. Nat Immunol 2000;1(5):398–401. [59] Simmons G, Reeves JD, Grogan CC, et al. DC-SIGN and DC-SIGNR bind ebola glycoproteins and enhance infection of macrophages and endothelial cells. Virology 2003;305(1):115–23. [60] Alvarez CP, Lasala F, Carrillo J, Muniz O, Corbi AL, Delgado R. C-type lectins DC-SIGN and L-SIGN mediate cellular entry by Ebola virus in cis and in trans. J Virol 2002;76(13):6841–4. [61] Mahanty S, Hutchinson K, Agarwal S, McRae M, Rollin PE, Pulendran B. Cutting edge: impairment of dendritic cells and adaptive im-

158

[62]

[63] [64]

[65]

[66]

[67]

[68]

[69]

[70]

[71]

[72] [73]

[74] [75] [76]

[77]

[78]

[79]

[80]

[81]

M. Larsson et al. / Seminars in Immunology 16 (2004) 147–161 munity by Ebola and Lassa viruses. J Immunol 2003;170(6):2797– 801. Bosio CM, Aman MJ, Grogan CC, et al. Ebola and Marburg viruses replicate in monocyte-derived dendritic cells without inducing the production of cytokines and full maturation. J Infect Dis 2003;188(11):1630–8. Lore K, Larsson M. The role of dendritic cells in the pathogenesis of HIV-1 infection. APMIS 2003;111(7/8):776–88. Andrieu M, Chassin D, Desoutter JF, et al. Downregulation of major histocompatibility class I on human dendritic cells by HIV Nef impairs antigen presentation to HIV-specific CD8+ T lymphocytes. AIDS Res Hum Retrovir 2001;17(14):1365–70. Donaghy H, Gazzard B, Gotch F, Patterson S. Dysfunction and infection of freshly isolated blood myeloid and plasmacytoid dendritic cells in patients infected with HIV-1. Blood 2003;101(11):4505–11. Larsson M, Fonteneau J, Lirvall M, Haslett P, Lifson J, Bhardwaj N. Activation of HIV-1 specific CD4+ and CD8+ T cells by human dendritic cells: roles of crosspresentation and noninfectious HIV-1 virus. AIDS 2002;16:1319–30. Takeuchi K, Miyajima N, Nagata N, Takeda M, Tashiro M. Wildtype measles virus induces large syncytium formation in primary human small airway epithelial cells by a SLAM(CD150)-independent mechanism. Virus Res 2003;94(1):11–6. Pope M, Betjes MG, Romani N, et al. Conjugates of dendritic cells and memory T lymphocytes from skin facilitate productive infection with HIV-1. Cell 1994;78(3):389–98. Larsson M, Fonteneau JF, Lee A, Bhardwaj N. Interations of viruses with dendritic cells. In: Lotze M, Thomson A, editors. Dendritic cells: biology and clinical applications. Academic Press; 2001. p. 505–22 [chapter 36]. Somersan S, Larsson M, Fonteneau JF, Basu S, Srivastava P, Bhardwaj N. Primary tumor tissue lysates are enriched in heat shock proteins and induce the maturation of human dendritic cells. J Immunol 2001;167(9):4844–52. Shi Y, Evans JE, Rock KL. Molecular identification of a danger signal that alerts the immune system to dying cells [comment]. Nature 2003;425(6957):516–21. Le Bon A, Tough DF. Links between innate and adaptive immunity via type I interferon. Curr Opin Immunol 2002;14(4):432–6. Beg AA. Endogenous ligands of Toll-like receptors: implications for regulating inflammatory and immune responses. Trends Immunol 2002;23(11):509–12. Barton GM, Medzhitov R. Toll-like receptor signaling pathways. Science 2003;300(5625):1524–5. Akira S. Toll-like receptor signaling. J Biol Chem 2003; 278(40):38105–8. Kawai T, Takeuchi O, Fujita T, et al. Lipopolysaccharide stimulates the MyD88-independent pathway and results in activation of IFN-regulatory factor 3 and the expression of a subset of lipopolysaccharide-inducible genes. J Immunol 2001;167(10):5887– 94. Doyle S, Vaidya S, O’Connell R, et al. IRF3 mediates a TLR3/ TLR4-specific antiviral gene program. Immunity 2002;17(3):251– 63. Yamamoto M, Sato S, Mori K, et al. Cutting edge: a novel Toll/IL-1 receptor domain-containing adapter that preferentially activates the IFN-beta promoter in the Toll-like receptor signaling. J Immunol 2002;169(12):6668–72. Oshiumi H, Matsumoto M, Funami K, Akazawa T, Seya T. TICAM-1 an adaptor molecule that participates in Toll-like receptor 3-mediated interferon-beta induction [comment]. Nat Immunol 2003;4(2):161–7. Kadowaki N, Ho S, Antonenko S, et al. Subsets of human dendritic cell precursors express different toll-like receptors and respond to different microbial antigens. J Exp Med 2001;194(6):863–9. Krug A, Towarowski A, Britsch S, et al. Toll-like receptor expression reveals CpG DNA as a unique microbial stimulus for plasmacytoid

[82]

[83]

[84]

[85]

[86]

[87]

[88]

[89]

[90]

[91]

[92]

[93]

[94]

[95]

[96]

[97]

[98] [99] [100]

dendritic cells which synergizes with CD40 ligand to induce high amounts of IL-12. Eur J Immunol 2001;31(10):3026–37. Jarrossay D, Napolitani G, Colonna M, Sallusto F, Lanzavecchia A. Specialization and complementarity in microbial molecule recognition by human myeloid and plasmacytoid dendritic cells. Eur J Immunol 2001;31(11):3388–93. Hornung V, Rothenfusser S, Britsch S, et al. Quantitative expression of toll-like receptor 1–10 mRNA in cellular subsets of human peripheral blood mononuclear cells and sensitivity to CpG oligodeoxynucleotides. J Immunol 2002;168(9):4531–7. Pulendran B, Kumar P, Cutler CW, Mohamadzadeh M, Van Dyke T, Banchereau J. Lipopolysaccharides from distinct pathogens induce different classes of immune responses in vivo. J Immunol 2001;167(9):5067–76. Lore K, Betts M, Brenchley J, et al. Toll-like receptor ligands modulate dendritic cells to augment cytomegalovirus- and HIV-1specific T cell responses. J Immunol 2003;171(8):4320–8. Servant MJ, Grandvaux N, Hiscott J. Multiple signaling pathways leading to the activation of interferon regulatory factor 3. Biochem Pharmacol 2002;64(5/6):985–92. Levy DE, Marie I, Prakash A. Ringing the interferon alarm: differential regulation of gene expression at the interface between innate and adaptive immunity. Curr Opin Immunol 2003;15(1): 52–8. Diebold SS, Montoya M, Unger H, et al. Viral infection switches non-plasmacytoid dendritic cells into high interferon producers. Nature 2003;424(6946):324–8. Kerkmann M, Rothenfusser S, Hornung V, et al. Activation with CpG-A and CpG-B oligonucleotides reveals two distinct regulatory pathways of type I IFN synthesis in human plasmacytoid dendritic cells. J Immunol 2003;170(9):4465–74. Takauji R, Iho S, Takatsuka H, et al. CpG-DNA-induced IFN-alpha production involves p38 MAPK-dependent STAT1 phosphorylation in human plasmacytoid dendritic cell precursors. J Leukoc Biol 2002;72(5):1011–9. Izaguirre A, Barnes BJ, Amrute S, et al. Comparative analysis of IRF and IFN-alpha expression in human plasmacytoid and monocytederived dendritic cells. J Leukoc Biol 2003;74(6):1125–38. Muzio M, Bosisio D, Polentarutti N, et al. Differential expression and regulation of toll-like receptors (TLR) in human leukocytes: selective expression of TLR3 in dendritic cells. J Immunol 2000;164(11):5998–6004. Honda K, Sakaguchi S, Nakajima C, et al. Selective contribution of IFN-alpha/beta signaling to the maturation of dendritic cells induced by double-stranded RNA or viral infection. Proc Natl Acad Sci USA 2003;100(19):10872–7. Lopez CB, Garcia-Sastre A, Williams BR, Moran TM. Type I interferon induction pathway, but not released interferon, participates in the maturation of dendritic cells induced by negative-strand RNA viruses. J Infect Dis 2003;187(7):1126–36. Suzuki N, Suzuki S, Yeh WC. IRAK-4 as the central TIR signaling mediator in innate immunity. Trends Immunol 2002;23(10): 503–6. Haynes LM, Moore DD, Kurt-Jones EA, Finberg RW, Anderson LJ, Tripp RA. Involvement of toll-like receptor 4 in innate immunity to respiratory syncytial virus. J Virol 2001;75(22):10730–7. Haeberle HA, Takizawa R, Casola A, et al. Respiratory syncytial virus-induced activation of nuclear factor-kappaB in the lung involves alveolar macrophages and toll-like receptor 4-dependent pathways. J Infect Dis 2002;186(9):1199–206. Kopp E, Medzhitov R. Recognition of microbial infectio by Tolllike receptors. Curr Opin Immunol 2003;15:396–401. Vaidya SA, Cheng G. Toll-like receptors and innate antiviral responses. Curr Opin Immunol 2003;15:402–7. Rassa JC, Ross SR. Viruses and Toll-like receptors. Microb Infect 2003;5(11):961–8.

M. Larsson et al. / Seminars in Immunology 16 (2004) 147–161 [101] Lund J, Sato A, Akira S, Medzhitov R, Iwasaki A. Toll-like receptor 9-mediated recognition of Herpes simplex virus-2 by plasmacytoid dendritic cells. J Exp Med 2003;198(3):513–20. [102] Krug A, Luker G, Barchet W, Akira S, Colonna M. Herpes Simplex Virus type 1 HSV-1 activates murine natural interferon-producing cells IPC through TollLike Receptor. Blood 2004;103(4):433–7. [103] Karlin S, Doerfler W, Cardon LR. Why is CpG suppressed in the genomes of virtually all small eukaryotic viruses but not in those of large eukaryotic viruses? J Virol 1994;68(5):2889–97. [104] Lee J, Chuang TH, Redecke V, et al. Molecular basis for the immunostimulatory activity of guanine nucleoside analogs: activation of Toll-like receptor 7. Proc Natl Acad Sci USA 2003;100(11):6646– 51. [105] Heil F, Ahmad-Nejad P, Hemmi H, et al. The Toll-like receptor 7 (TLR7)-specific stimulus loxoribine uncovers relationship within the TLR7, 8 and 9 subfamily. Eur J Immunol 2003;33(11):2987–97. [106] Matsumoto M, Funami K, Tanabe M, et al. Subcellular localization of toll-like receptor 3 in human dendritic cells. J Immunol 2003;171(6):3154–62. [107] Miettinen M, Sareneva T, Julkunen I, Matikainen S. IFNs activate toll-like receptor gene expression in viral infections. Genes Immun 2001;2(6):349–55. [108] Tanabe M, Kurita-Taniguchi M, Takeuchi K, et al. Mechanism of up-regulation of human Toll-like receptor 3 secondary to infection of measles virus-attenuated strains. Biochem Biophys Res Commun 2003;311(1):39–48. [109] Bowie A, Kiss-Toth E, Symons JA, Smith GL, Dower SK, O’Neill LA. A46R and A52R from vaccinia virus are antagonists of host IL-1 and toll-like receptor signaling [comment]. Proc Natl Acad Sci USA 2000;97(18):10162–7. [110] Harte MT, Haga IR, Maloney G, et al. The poxvirus protein A52R targets Toll-like receptor signaling complexes to suppress host defense. J Exp Med 2003;197(3):343–51. [111] Geijtenbeek TB, Kwon DS, Torensma R, et al. DC-SIGN, a dendritic cell-specific HIV-1-binding protein that enhances trans-infection of T cells [comment]. Cell 2000;100(5):587–97. [112] Soilleux EJ, Morris LS, Leslie G, et al. Constitutive and induced expression of DC-SIGN on dendritic cell and macrophage subpopulations in situ and in vitro. J Leukoc Biol 2002;71(3):445– 57. [113] Lozach PY, Lortat-Jacob H, de Lacroix de Lavalette A, et al. DCSIGN and L-SIGN are high affinity binding receptors for hepatitis C virus glycoprotein E2. J Biol Chem 2003;278(22):20358–66. [114] Blomberg S, Eloranta ML, Magnusson M, Alm GV, Ronnblom L. Expression of the markers BDCA-2 and BDCA-4 and production of interferon-alpha by plasmacytoid dendritic cells in systemic lupus erythematosus. Arthritis Rheum 2003;48(9):2524–32. [115] Dzionek A, Inagaki Y, Okawa K, et al. Plasmacytoid dendritic cells: from specific surface markers to specific cellular functions. Hum Immunol 2002;63(12):1133–48. [116] Le Bon A, Etchart N, Rossmann C, et al. Cross-priming of CD8+ T cells stimulated by virus-induced type I interferon [comment]. Nat Immunol 2003;4(10):1009–15. [117] Goodbourn S, Didcock L, Randall RE. Interferons: cell signalling, immune modulation, antiviral response and virus countermeasures. J Gen Virol 2000;81(Pt 10):2341–64. [118] Samuel CE. Antiviral actions of interferons. Clin Microbiol Rev 2001;14(4):778–809. [119] Horng T, Barton GM, Medzhitov R. TIRAP: an adapter molecule in the Toll signaling pathway [comment]. Nat Immunol 2001;2(9):835– 41. [120] Sauder DN, Smith MH, Senta-McMillian T, Soria I, Meng TC. Randomized, single-blind, placebo-controlled study of topical application of the immune response modulator resiquimod in heathly adults. Antimicrob Agents Chemother 2003;47(12):3846–52. [121] Bottrel RL, Yang YL, Levy DE, Tomai M, Reis LF. The immune response modifier imiquimod requires STAT-1 for induction of in-

[122]

[123]

[124]

[125]

[126]

[127]

[128] [129]

[130]

[131] [132] [133]

[134] [135]

[136]

[137]

[138]

[139]

[140]

[141]

159

terferon, interferon-stimulated genes, and interleukin-6. Antimicrob Agents Chemother 1999;43(4):856–61. Garcia-Sastre A. Mechanisms of inhibition of the host interferon alpha/beta-mediated antiviral responses by viruses. Microb Infect 2002;4(6):647–55. Basler CF, Garcia-Sastre A. Viruses and the type I interferon antiviral system: induction and evasion. Int Rev Immunol 2002;21(4/5):305–37. de la Rosa G, Longo N, Rodriguez-Fernandez JL, et al. Migration of human blood dendritic cells across endothelial cell monolayers: adhesion molecules and chemokines involved in subset-specific transmigration. J Leukoc Biol 2003;73(5):639–49. Penna G, Vulcano M, Sozzani S, Adorini L. Differential migration behavior and chemokine production by myeloid and plasmacytoid dendritic cells. Hum Immunol 2002;63(12):1164–71. Vanbervliet B, Bendriss-Vermare N, Massacrier C, et al. The inducible CXCR3 ligands control plasmacytoid dendritic cell responsiveness to the constitutive chemokine stromal cell-derived factor 1 (SDF-1)/CXCL12. J Exp Med 2003;198(5):823–30. Sallusto F, Lanzavecchia A. Mobilizing dendritic cells for tolerance, priming, and chronic inflammation [comment]. J Exp Med 1999;189(4):611–4. Haig DM. Subversion and piracy: DNA viruses and immune evasion. Res Vet Sci 2001;70(3):205–19. Hermans IF, Silk JD, Gileadi U, et al. NKT cells enhance CD4+ and CD8+ T cell responses to soluble antigen in vivo through direct interaction with dendritic cells. J Immunol 2003;171(10):5140–7. Levy O, Orange JS, Hibberd P, et al. Disseminated varicella infection due to the vaccine strain of varicella-zoster virus, in a patient with a novel deficiency in natural killer T cells. J Infect Dis 2003;188(7):948–53. Skold M, Behar SM. Role of CD1d-restricted NKT cells in microbial immunity. Infect Immun 2003;71(10):5447–55. Biron CA, Brossay L. NK cells and NKT cells in innate defense against viral infections. Curr Opin Immunol 2001;13(4):458–64. Yokoyama WM, Scalzo AA. Natural killer cell activation receptors in innate immunity to infection. Microb Infect 2002;4(15):1513– 21. Diefenbach A, Raulet DH. Strategies for target cell recognition by natural killer cells. Immunol Rev 2001;181:170–84. Wilson JL, Heffler LC, Charo J, Scheynius A, Bejarano MT, Ljunggren HG. Targeting of human dendritic cells by autologous NK cells. J Immunol 1999;163(12):6365–70. Matikainen S, Paananen A, Miettinen M, et al. IFN-alpha and IL-18 synergistically enhance IFN-gamma production in human NK cells: differential regulation of Stat4 activation and IFN-gamma gene expression by IFN-alpha and IL-12. Eur J Immunol 2001;31(7):2236– 45. Strengell M, Matikainen S, Siren J, et al. IL-21 in synergy with IL-15 or IL-18 enhances IFN-gamma production in human NK and T cells. J Immunol 2003;170(11):5464–9. Nguyen KB, Salazar-Mather TP, Dalod MY, et al. Coordinated and distinct roles for IFN-alpha beta, IL-12, and IL-15 regulation of NK cell responses to viral infection. J Immunol 2002;169(8):4279–87. Gerosa F, Baldani-Guerra B, Nisii C, Marchesini V, Carra G, Trinchieri G. Reciprocal activating interaction between natural killer cells and dendritic cells. J Exp Med 2002;195(3):327–33. Ferlazzo G, Tsang ML, Moretta L, Melioli G, Steinman RM, Munz C. Human dendritic cells activate resting natural killer (NK) cells and are recognized via the NKp30 receptor by activated NK cells. J Exp Med 2002;195(3):343–51. Terrazzano G, Zanzi D, Palomba C, et al. Differential involvement of CD40, CD80, and major histocompatibility complex class I molecules in cytotoxicity induction and interferon-gamma production by human natural killer effectors. J Leukoc Biol 2002;72(2):305–11.

160

M. Larsson et al. / Seminars in Immunology 16 (2004) 147–161

[142] Nishioka Y, Nishimura N, Suzuki Y, Sone S. Human monocytederived and CD83(+) blood dendritic cells enhance NK cellmediated cytotoxicity. Eur J Immunol 2001;31(9):2633–41. [143] Mailliard RB, Son YI, Redlinger R, et al. Dendritic cells mediate NK cell help for Th1 and CTL responses: two-signal requirement for the induction of NK cell helper function. J Immunol 2003;171(5): 2366–73. [144] Mocikat R, Braumuller H, Gumy A, et al. Natural killer cells activated by MHC class I (low) targets prime dendritic cells to induce protective CD8 T cell responses. Immunity 2003;19(4): 561–9. [145] Orange JS, Fassett MS, Koopman LA, Boyson JE, Strominger JL. Viral evasion of natural killer cells. Nat Immunol 2002;3(11):1006– 12. [146] Yonezawa A, Morita R, Takaori-Kondo A, et al. Natural alpha interferon-producing cells respond to human immunodeficiency virus type 1 with alpha interferon production and maturation into dendritic cells. J Virol 2003;77(6):3777–84. [147] Feldman SB, Ferraro M, Zheng HM, Patel N, Gould-Fogerite S, Fitzgerald-Bocarsly P. Viral induction of low frequency interferonalpha producing cells. Virology 1994;204(1):1–7. [148] Gary-Gouy H, Lebon P, Dalloul AH. Type I interferon production by plasmacytoid dendritic cells and monocytes is triggered by viruses, but the level of production is controlled by distinct cytokines. J Interferon Cytokine Res 2002;22(6):653–9. [149] Rissoan MC, Soumelis V, Kadowaki N, et al. Reciprocal control of T helper cell and dendritic cell differentiation [comment]. Science 1999;283(5405):1183–6. [150] Payvandi F, Amrute S, Fitzgerald-Bocarsly P. Exogenous and endogenous IL-10 regulate IFN-alpha production by peripheral blood mononuclear cells in response to viral stimulation. J Immunol 1998;160(12):5861–8. [151] Soumelis V, Scott I, Liu YJ, Levy J. Natural type 1 interferon producing cells in HIV infection. Hum Immunol 2002;63(12):1206– 12. [152] Banchereau J, Steinman RM. Dendritic cells and the control of immunity. Nature 1998;392:245–52. [153] Sallusto F, Mackay CR, Lanzavecchia A. The role of chemokine receptors in primary, effector, and memory immune responses. Annu Rev Immunol 2000;18:593–620. [154] Wu SJ, Grouard-Vogel G, Sun W, et al. Human skin Langerhans cells are targets of dengue virus infection [comment]. Nat Med 2000;6(7):816–20. [155] Rong Q, Alexander TS, Koski GK, Rosenthal KS. Multiple mechanisms for HSV-1 induction of interferon alpha production by peripheral blood mononuclear cells. Arch Virol 2003;148(2):329–44. [156] Samady L, Costigliola E, MacCormac L, et al. Deletion of the virion host shutoff protein (vhs) from herpes simplex virus (HSV) relieves the viral block to dendritic cell activation: potential of vhsHSV vectors for dendritic cell-mediated immunotherapy. J Virol 2003;77(6):3768–76. [157] Herr W, Ranieri E, Olson W, Zarour H, Gesualdo L, Storkus WJ. Mature dendritic cells pulsed with freeze-thaw cell lysates define an effective in vitro vaccine designed to elicit EBV-specific CD4(+) and CD8(+) T lymphocyte responses. Blood 2000;96:1857– 64. [158] Subklewe M, Paludan C, Tsang ML, Steinman RM, Münz C. Dendritic cells cross-present latency gene products from EpsteinBarr Virus-transformed B cells and expand tumor-reactive CD8(+) killer T cells. J Exp Med 2001;193:405–12. [159] Arrode G, Davrinche C. Dendritic cells and HCMV crosspresentation. Curr Top Microbiol Immunol 2003;276:277–94. [160] Arrode G, Boccaccio C, Abastado JP, Davrinche C. Crosspresentation of human cytomegalovirus pp65 (UL83) to CD8+ T cells is regulated by virus-induced, soluble-mediator-dependent maturation of dendritic cells. J Virol 2002;76(1):142–50.

[161] Moutaftsi M, Mehl AM, Borysiewicz LK, Tabi Z. Human cytomegalovirus inhibits maturation and impairs function of monocyte-derived dendritic cells. Blood 2002;99(8):2913–21. [162] Drillien R, Spehner D, Bohbot A, Hanau D. Vaccinia virus-related events and phenotypic changes after infection of dendritic cells derived from human monocytes. Virology 2000;268(2):471–81. [163] Larsson M, Fonteneau JF, Somersan S, et al. Efficiency of cross presentation of vaccinia virus-derived antigens by human dendritic cells. Eur J Immunol 2001;31(12):3432–42 [erratum appears in Eur J Immunol 2002;32(1):307]. [164] Ramirez MC, Sigal LJ. Macrophages and dendritic cells use the cytosolic pathway to rapidly cross-present antigen from live, vacciniainfected cells. J Immunol 2002;169(12):6733–42. [165] Geisbert TW, Hensley LE, Larsen T, et al. Pathogenesis of Ebola hemorrhagic fever in cynomolgus macaques: evidence that dendritic cells are early and sustained targets of infection. Am J Pathol 2003;163(6):2347–70. [166] Klagge IM, Schneider-Schaulies S. Virus interactions with dendritic cells. J Gen Virol 1999;80(Pt 4):823–33. [167] Barron MA, Blyveis N, Palmer BE, MaWhinney S, Wilson CC. Influence of plasma viremia on defects in number and immunophenotype of blood dendritic cell subsets in human immunodeficiency virus 1-infected individuals. J Infect Dis 2003;187(1):26–37. [168] Kobelt D, Lechmann M, Steinkasserer A. The interaction between dendritic cells and herpes simplex virus-1. Curr Top Microbiol Immunol 2003;276:145–61. [169] Ploegh HL. Viral strategies of immune evasion. Science 1998;280:248–53. [170] Petersen JL, Morris CR, Solheim JC. Virus evasion of MHC class I molecule presentation. J Immunol 2003;171(9):4473–8. [171] Weber F, Kochs G, Haller O, Staeheli P. Viral evasion of the interferon system: old viruses, new tricks. J Interferon Cytokine Res 2003;23(4):209–13. [172] Dubois B, Lamy PJ, Chemin K, Lachaux A, Kaiserlian D. Measles virus exploits dendritic cells to suppress CD4+ T-cell proliferation via expression of surface viral glycoproteins independently of Tcell trans-infection. Cell Immunol 2001;214(2):173–83. [173] Vidalain PO, Azocar O, Lamouille B, Astier A, Rabourdin-Combe C, Servet-Delprat C. Measles virus induces functional TRAIL production by human dendritic cells. J Virol 2000;74(1):556–9. [174] Larsson M, Fonteneau JF, Bhardwaj N. Dendritic cells resurrect antigens from dead cells. Trends Immunol 2001;22(3):141–8. [175] Larsson M, Fonteneau JF, Bhardwaj N. Cross-presentation of cellassociated antigens by dendritic cells. Curr Top Microbiol Immunol 2003;276:261–75. [176] Bevan MJ. Cross-priming for a secondary cytotoxic response to minor H antigens with H-2 congenic cells which do not cross-react in the cytotoxic assay. J Exp Med 1976;143:1283–8. [177] Heath WR, Carbone FR. Cross-presentation, dendritic cells, tolerance and immunity. Annu Rev Immunol 2001;19:47–64. [178] Heath WR, Kurts C, Miller JFAP, Carbone F. Cross-tolerance: a pathway for inducing tolerance to peripheral tissue antigens. J Exp Med 1998;187:1549–53. [179] Huang F-P, Platt N, Wykes M, et al. A discrete subpopulation of dendritic cells transports apoptotic intestinal epithelial cells to T cell areas of mesenteric lymph nodes. J Exp Med 2000;191:435–44. [180] Sigal LJ, Rock KL. Bone marrow-derived antigen-presenting cells are required for the generation of cytotoxic T lymphocyte responses to viruses and use transporter associated with antigen presentation (TAP)-dependent and -independent pathways of antigen presentation. J Exp Med 2000;192:1143–50. [181] Sotomayor EM, Borrello I, Rattis F-M, Abrams J, StaveleyO’Carroll K, Levitsky HI. Cross-presentation of tumor by bone marrow derived antigen presenting cells is the dominant mechanism in the induction of T cell tolerance during B-cell lymphoma progression. Blood 2001;98(4):1070–7.

M. Larsson et al. / Seminars in Immunology 16 (2004) 147–161 [182] Bennett SRM, Carbone FR, Karamalis F, Flavell RA, Miller JFAP, Heath WR. Help for cytotoxic-T-cell responses is mediated by CD40 signalling. Nature 1998;393:478–80. [183] den Haan J, Lehar S, Bevan M. CD8+ but not CD8− dendritic cells cross-prime cytotoxic T cells in vivo. J Exp Med 2000;192: 1685–96. [184] Pooley JL, Heath WR, Shortman K. Intravenous soluble antigen is presented to CD4 T cells by CD8(−) dendritic cells but crosspresented to CD8 T cells by CD8+ dendritic cells. J Immunol 2001;166:5327–30. [185] Albert ML, Sauter B, Bhardwaj N. Dendritic cells acquire antigen from apoptotic cells and induce class I-restricted CTLs. Nature 1998;392:86–9. [186] Rodriguez A, Regnault A, Kleijmeer M, Ricciardi-Castagnoli P, Amigorena S. Selective transport of internalized antigens to the cytosol for MHC class I presentation in dendritic cells. Nat Cell Biol 1999;1:362–8. [187] Li M, Davey GM, Sutherland RM, et al. Cell-associated ovalbumin is cross-presented much more efficiently than soluble ovalbumin in vivo. J Immunol 2001;166:6099–103. [188] Machy P, Serre K, Leserman L. Class I-restricted presentation of exogenous antigen acquired by Fcgamma receptor-mediated endocytosis is regulated in dendritic cells. Eur J Immunol 2000;30:848– 57. [189] Tabi Z, Moutaftsi M, Borysiewicz LK. Human cytomegalovirus pp65- and immediate early 1 antigen-specific HLA class I-restricted cytotoxic T cell responses induced by cross-presentation of viral antigens. J Immunol 2001;166:5695–703.

161

[190] Arrode G, Boccaccio C, Lule J, et al. Incoming human cytomegalovirus pp65 (UL83) contained in apoptotic infected fibroblasts is cross-presented to CD8(+) T cells by dendritic cells. J Virol 2000;74(21):10018–24. [191] Ferlazzo G, Semino C, Spaggiari GM, Meta M, Mingari MC, Melioli G. Dendritic cells efficiently cross-prime HLA class Irestricted cytolytic T lymphocytes when pulsed with both apoptotic and necrotic cells but not with soluble cell-derived lysates. Int Immunol 2000;12(12):1741–7. [192] Popescu I, Macedo C, Zeevi A, et al. Ex vivo priming of naive T cells into EBV-specific Th1/Th2 effector cells by mature dendritic cells loaded with apoptotic/necrotic LCL. Am J Transplant 2003;3(11):1369–77. [193] Robinson HL. New hope for an AIDS vaccine. Nat Rev Immunol 2002;2(4):239–50. [194] Lundstrom K. Latest development in viral vectors for gene therapy. Trends Biotechnol 2003;21(3):117–22. [195] Jooss K, Chirmule N. Immunity to adenovirus and adenoassociated viral vectors: implications for gene therapy. Gene Ther 2003;10(11):955–63. [196] Amara RR, Robinson HL. A new generation of HIV vaccines. Trends Mol Med 2002;8(10):489–95. [197] Lundstrom K. Alphavirus vectors for vaccine production and gene therapy. Exp Rev Vacc 2003;2(3):447–59. [198] Polo JM, Gardner JP, Ji Y, et al. Alphavirus DNA and particle replicons for vaccines and gene therapy. Dev Biol 2000;104:181–5.