Vaccination is among the most efficient forms of immunotherapy. Although sometimes inducing lifelong protective B-cell responses, T-cell–mediated immunity remains challenging. Targeting antigen to dendritic cells (DCs) is an extensively explored concept aimed at improving cellular immunity. The identification of various DC subsets with distinct functional characteristics now allows for the fine-tuning of targeting strategies. Although some of these DC subsets are regarded as superior for (cross-) priming of naive T cells, controversies still remain about which subset represents the best target for immunotherapy. Because targeting the antigen alone may not be sufficient to obtain effective T-cell responses, delivery systems have been developed to target multiple vaccine components to DCs. In this Perspective, we discuss the pros and cons of targeting DCs: if targeting is beneficial at all and which vaccine vehicles and immunization routes represent promising strategies to reach and activate DCs.

Classic vaccines are among the most cost-effective public health interventions and provide a good example of effective immunotherapy. Their development has been one of trial and error spanning several centuries. Initially, farm animals and humans were inoculated with serous fluid from infected individuals to protect against infectious diseases.1  In the late 18th century, Jenner published a relatively safe immunization strategy, using cowpox to provide cross-immunity against smallpox in humans.2  Many governments worldwide rapidly implemented this procedure, acknowledging its potential to reduce the devastating effect of epidemics on the general population. In the 19th century, Pasteur generated artificially weakened pathogens and used them for vaccination against rabies and anthrax.1  Adjuvants were introduced in the 20th century by Ramon, who showed that vaccine efficacy was enhanced by the addition of substances such as bread crumbs, tapioca, starch oil, or saponin.3  Aluminum salts (alum) were among the first adjuvants to be applied and remain, to date, the most common adjuvant in prophylactic vaccines.4  For decades, alum was the only adjuvant licensed for human use, but its mechanisms of action are only now being understood.5 

Despite successful application in many vaccines, the use of alum is limited to vaccines aiming to induce Th2-type immunity. These classic prophylactic vaccines focus mainly on the induction of long-lived T-helper cell–dependent IgG responses. However, therapeutic vaccines for treatment of chronic infections and cancer require strong proinflammatory CD4+ and CD8+ T-cell responses.6  Advanced knowledge in the molecular and cellular mechanisms underlying effective immune responses has revolutionized vaccine development over the past decades. Last year’s Nobel Laureates Beutler, Hoffman, and Steinman made seminal contributions to the two pillars that form the basis of present-day rational vaccine design. Together, with important work by Medzhitov and Janeway, Beutler and Hoffman discovered how Toll-like receptors (TLRs) activate immune cells. This resulted in the broad range of TLR agonists that are currently explored in clinical trials. Steinman discovered the dendritic cell (DC), the key antigen presenting cell (APC) orchestrating adaptive immune responses that is particularly important in effectuating potent CD4+ and CD8+ T-cell responses. Steinman’s work formed the basis for cellular vaccines, such as the licensed Sipuleucel-T,7  and for vaccines specifically targeting antigens to DC surface receptors.8 

Although it seems logical in vaccine design to focus on DCs as the most potent APCs, the identification of various subsets complicate the choice.9  Immunologists are vigorously attempting to unravel the biological properties of these subsets to learn how to best reach and activate them, and thus to improve vaccine design. In this Perspective, we discuss recent findings and provide guiding principles for the development of novel vaccine strategies.

Most classical vaccines are administered intramuscularly or subcutaneously, where they attract various types of APCs. Upon activation, these APCs begin migrating to the lymph nodes to activate T cells. Depending on the vaccine formulation, particular APC subsets release specific cytokines that contribute to the polarization and fine-tuning of T-cell immunity.10  The concept of direct targeting of DC subsets in situ overcomes the need for cell migration and facilitates the instant delivery of antigen to (cross-) presenting resident DC subsets in the spleen and the lymph nodes. Thus, vaccine components are delivered directly to those APCs that are most potent in mediating CD4+ and CD8+ T-cell immunity. To this end, researchers exploit the differential expression of both intra- and extracellular receptors by DC subsets (Table 1). Many of these receptors are pathogen recognition receptors (PRRs), including C-type lectin receptors (CLRs) and TLRs. While CLRs function mainly as the address label to reach a specific subset, TLRs are used as a target for cell activation.

Table 1

DC subsets and their properties are grouped by the most prominently associated induced T-cell response

Immune responseDC subsetUptake receptorTLRCross-presentationComments
Th1 BDCA3+ H CD8α+ M Clec9A, LangerinM, DEC-205, Clec12A, DCAR1M 1, 2, 3, 4M, 6, 8, 9M ++ Treg47  
Langerhans Langerin, DEC-205, Dectin1, Dectin2, DCIRH 1H, 2, 3, 4M, 6H,M?, 9M CTL induction or licensing97 
Th2, Th17, Th22 
Dermal CD1a+ H Dermal CD103+ M Langerin, DEC-205, MGLH, DCIRH 3M, 4H ++ Th1798  
Th2 BDCA1+ H CD8α− M DCIR2M, Clec12A, DCIR, Dectin-1H, DEC-205H, mMGL1M, 2M1, 2, 3H, 4, 5, 6, 7, 8, 9M  
Th1/Th2 moDCH DC-SIGN, DEC-205, MR, DCIR 1, 2, 3, 4, 5, 6, 8, 10 ++ Th17 
IFN-I pDC Siglec-H, BST-2, BDCA-2H, Clec9AM, Clec12A, Dectin-2, DEC-205H, DCIRH, Dectin-1M, mMGL1M 1H,M?, 6H,M?, 7, 9 Activation of myeloid DC and NK, B and T cells 
Immune responseDC subsetUptake receptorTLRCross-presentationComments
Th1 BDCA3+ H CD8α+ M Clec9A, LangerinM, DEC-205, Clec12A, DCAR1M 1, 2, 3, 4M, 6, 8, 9M ++ Treg47  
Langerhans Langerin, DEC-205, Dectin1, Dectin2, DCIRH 1H, 2, 3, 4M, 6H,M?, 9M CTL induction or licensing97 
Th2, Th17, Th22 
Dermal CD1a+ H Dermal CD103+ M Langerin, DEC-205, MGLH, DCIRH 3M, 4H ++ Th1798  
Th2 BDCA1+ H CD8α− M DCIR2M, Clec12A, DCIR, Dectin-1H, DEC-205H, mMGL1M, 2M1, 2, 3H, 4, 5, 6, 7, 8, 9M  
Th1/Th2 moDCH DC-SIGN, DEC-205, MR, DCIR 1, 2, 3, 4, 5, 6, 8, 10 ++ Th17 
IFN-I pDC Siglec-H, BST-2, BDCA-2H, Clec9AM, Clec12A, Dectin-2, DEC-205H, DCIRH, Dectin-1M, mMGL1M 1H,M?, 6H,M?, 7, 9 Activation of myeloid DC and NK, B and T cells 

Expression of uptake receptors and TLRs as well as cross-presentation potential is of further importance in the choice of suitable targets. M, mouse; H, human

CLRs facilitate receptor-mediated endocytosis by binding to carbohydrate ligands.11  Although the first targeting experiments involving MHC class II molecules and Fc receptors were carried out in the late 1980s,12,13  the field really kicked off at the beginning of the new millennium with the discovery of many new CLRs on DCs. It was at this time that Steinman and his colleagues first described the targeting properties of antibodies, which recognize the CLR Dec205.14,15  Many more groups subsequently followed this approach and studied a plethora of receptors present on APCs as possible targets for antigen uptake and subsequent (cross-) presentation (Table 2).16-21  A prominent example is the CLR Clec9a that has not only been exploited for antigen targeting, but was recently also shown to bind to filamentous actin released by dying and necrotic cells.22-24  Clec9a was further shown to play a crucial role in antiviral immunity by cross-presentation of virus-infected dead cell material.25,26 

Table 2

Overview of vaccine targeting approaches

VaccineSpeciesTargeting moietyAdjuvantAdjuvant- antigen linked?Reference
Protein conjugate Mouse αDec-205 Ab αCD40 Ab, MALP-2, No 16,78  
Pam3Cys, polyI:C, polyICLC 
LPS, R848, CpG 
 CpG Yes 93  
αMR Ab CpG No 17  
αLangerin Ab PolyI:C, PolyICLC, αCD40 Ab No 60  
αDC-SIGN Ab None No 99  
αDectin-1 Ab PolyI:C No 18  
αClec9A Ab PolyI:C, PolyICLC, αCD40 Ab, No 60,34,100  
 Curdlan   
αSiglec-H Ab CpG No 29,30  
Lewis-X or -B* None No 101  
Tn antigen CpG, alum, αCD40 Ab No 19  
αBST-2 Ab PolyI:C No 28  
Human αDec-205 Ab CD40 Ligand No 102  
αMR Ab R848, MALP-2, Loxoribine, No 103  
 Pam3CSK4, Flagellin, LPS,   
 PolyI:C, CD40 Ligand   
αDC-SIGN Ab PolyI:C, R848 No 20  
αDCIR Ab PolyI:C, LPS, CL075, CD40 No 21,104  
 Ligand, CpG-C, Loxoribine   
αClec9A Ab PolyI:C, R848 No 44,105  
Oxidized mannan None No  
Polymer particle Mouse αDec-205 Ab Particle composition Yes 106  
αDec-205 Ab PolyI:C, R848 Yes 91  
Human αDC-SIGN Ab PolyI:C, R848 Yes 91  
Liposome Mouse αDec-205 Ab IFNγ or LPS Yes 96  
Mannose Pam3CAG, Pam2CAG, Yes 66  
 Pam2CGD   
Lewis-X or -B* — — 107  
Lewis A or tri- — — 108  
GlcNAc    
Mannopentaose — — 109  
Human αDec-205 Ab — — 110  
αDC-SIGN Ab — — 111  
Virus Mouse CD40 Ligand CD40 Ligand Yes 95  
Mutated Sindbis — — 94  
Virus glycoprotein*    
Human αDC-SIGN Ab — — 112  
αCD40 scFv αCD40 scFv No 113  
CD40 Ligand CD40 Ligand Yes 114  
VaccineSpeciesTargeting moietyAdjuvantAdjuvant- antigen linked?Reference
Protein conjugate Mouse αDec-205 Ab αCD40 Ab, MALP-2, No 16,78  
Pam3Cys, polyI:C, polyICLC 
LPS, R848, CpG 
 CpG Yes 93  
αMR Ab CpG No 17  
αLangerin Ab PolyI:C, PolyICLC, αCD40 Ab No 60  
αDC-SIGN Ab None No 99  
αDectin-1 Ab PolyI:C No 18  
αClec9A Ab PolyI:C, PolyICLC, αCD40 Ab, No 60,34,100  
 Curdlan   
αSiglec-H Ab CpG No 29,30  
Lewis-X or -B* None No 101  
Tn antigen CpG, alum, αCD40 Ab No 19  
αBST-2 Ab PolyI:C No 28  
Human αDec-205 Ab CD40 Ligand No 102  
αMR Ab R848, MALP-2, Loxoribine, No 103  
 Pam3CSK4, Flagellin, LPS,   
 PolyI:C, CD40 Ligand   
αDC-SIGN Ab PolyI:C, R848 No 20  
αDCIR Ab PolyI:C, LPS, CL075, CD40 No 21,104  
 Ligand, CpG-C, Loxoribine   
αClec9A Ab PolyI:C, R848 No 44,105  
Oxidized mannan None No  
Polymer particle Mouse αDec-205 Ab Particle composition Yes 106  
αDec-205 Ab PolyI:C, R848 Yes 91  
Human αDC-SIGN Ab PolyI:C, R848 Yes 91  
Liposome Mouse αDec-205 Ab IFNγ or LPS Yes 96  
Mannose Pam3CAG, Pam2CAG, Yes 66  
 Pam2CGD   
Lewis-X or -B* — — 107  
Lewis A or tri- — — 108  
GlcNAc    
Mannopentaose — — 109  
Human αDec-205 Ab — — 110  
αDC-SIGN Ab — — 111  
Virus Mouse CD40 Ligand CD40 Ligand Yes 95  
Mutated Sindbis — — 94  
Virus glycoprotein*    
Human αDC-SIGN Ab — — 112  
αCD40 scFv αCD40 scFv No 113  
CD40 Ligand CD40 Ligand Yes 114  

Representative targeting studies are grouped by vaccine design. In addition, information on the presence and form of adjuvant in the vaccine formulations of these studies is depicted.

*

Binds to DC-SIGN.

Binds to MGL.

Binds to MR.

However, Clec9a gained its popularity as a putative target because of its more restricted expression by CD8α+ DCs (and plasmacytoid [p] DCs) in the mouse. The CD8α+ DC subset is described in many studies as particularly suited and well-equipped for the cross-presentation of antigen and priming of cytotoxic T lymphocytes (CTLs).27  Therefore, this DC subset is an interesting target for the induction of cellular immunity to fight diseases where strong Th1 responses are regarded as essential. Although pDCs are also implicated in antigen presentation to CD8+ T cells upon antigen targeting to pDC surface receptors,28-30  this cell type’s most striking feature is its potential to produce vast amounts of IFN I, which is crucial for antiviral defense.31  Because monocyte-derived DCs (moDCs), CD8α– DCs, and macrophages were also reported to cross-prime antigen to CD8+ T cells, CLRs expressed by these cell types might gain interest.32,33  Although these studies demonstrate the cross-presentation potential of other cell types, there is compelling evidence for a privileged role for CD8α+ DCs to function as major inducers of potent CTL responses in the murine system.

In humans, the situation is less clear, because only minute numbers of DCs can be gained from blood or from scarce lymphoid material, which complicates research. Recently, BDCA3+ DCs were described as the putative human equivalent of mouse CD8α+ DCs. This was based on phenotypic characteristics, the expression of particular transcription factors,34-38  and the fact that they cross-present antigen to CD8+ T cells.39-44  In addition to BDCA3+ DCs, blood-derived CD1c+ DCs, CD16+ DCs, and moDCs cross-present antigen to specific T-cell clones, albeit to a lesser extent.39,41,42  A study using cells derived from human spleens confirms that cross-presentation is not restricted to BDCA3+ DCs but shared with CD1b/c+ and CD16+ DCs.45  Yet, BDCA3+ (CD141+) DCs isolated from lung, liver, or dermis, or from the migratory fraction of skin-draining lymph nodes, were found to be superior cross-presenters of soluble antigen.46  Despite the fact that they have been exploited mainly for immunostimulation, a recent study reported that BDCA3+ DCs suppressed immune responses by the constitutive production of IL-10 and the induction of regulatory T cells.47  These findings, and other studies reporting cross-presentation of various forms of antigen by pDCs48-50  and CD1a– skin-draining lymph node resident DCs,51  raise the question of whether one universal vaccine target actually exists in humans. Table 1 provides an overview of DC subsets with their respective properties and functions. This can serve as orientation for the choice of target DC subset when aiming at specific immune responses.

TLRs on the other hand represent triggers to mediate adjuvanticity in modern vaccine formulation. Their ligation results in MyD88- or TRIF-dependent signaling and, thus, in the activation of APCs. Such activation in combination with antigenic uptake allows for direct priming of CTLs. Depending on their cellular location, TLRs are specialized in the detection of either extracellular or intracellular pathogens. Intracellular TLRs, which recognize different classes of nucleic acids, are considered particularly efficient targets for well-defined synthetic vaccine adjuvants. Prominent examples are the dsRNA mimetic polyinosinic:polycytidylic acid (polyI:C) as TLR3 agonist that induces type I IFNs and inflammatory cytokines,52  the imidazoquinolines imiquimod and R848 and synthetic polyU strands, which induce signaling by TLRs 7 and/or 8,53-55  and CpG DNA constituting a TLR9 agonist.56,57  Among these adjuvants, imiquimod and polyICLC, a derivative of polyI:C, revealed therapeutic potential in vaccination approaches for cancer, allergy, and infectious diseases in clinical trials. For the design of vaccination strategies, it is important to bear in mind that there are differences in the expression of TLRs between mouse and human DCs. One example is the absence of TLR9 in many human DC subsets considered to be interesting targets for vaccination approaches (Table 1).

Initial clinical trials investigating antigen targeting to APCs, in combination with TLR ligands (TLR-Ls) as adjuvants, are in progress. One encouraging example of targeting APCs is the phase I study by Morse et al., in which targeting of the human chorionic gonadotropin-β chain to the mannose receptor, when coadministered with the growth factor granulocyte macrophage–colony-stimulating factor and the TLR-Ls R848 (resiquimod) and polyICLC, resulted in antigen-specific cellular and humoral immunity.8 

To induce immunity rather than tolerance, it is necessary to have an activation signal in addition to the antigen. This concept appears to also apply for studies in which antigen is targeted to surface receptors: the presence of adjuvant induces the activation of effector T cells, whereas in contrast the absence of adjuvant results in immunosuppression.58,59  Interestingly, Idoyaga et al found no difference in the targeting of antigen to different receptors on the same cell in the presence of adjuvant.60  Thus, this ratifies immunostimulatory approaches using various CLRs as mere address labels and has shifted the focus of vaccine design to the DC subsets and how to activate them. Whether such activation should be supplied by mere coadministration of a stimulus, or whether antigen and adjuvant should be physically linked to ensure codelivery to the same cell, still remains a point of discussion. A recent study using nanoparticles to deliver antigen and adjuvant showed better humoral responses upon injection of both agents in separate particles than when combined in a single particle.61  Nevertheless, many studies aiming to induce cellular responses show that physically linking the antigen and adjuvant improves T-cell responses. In addition to chemically cross-linking the components,62,63  studies also compared the concept of packaging antigen and adjuvants into vehicles, such as polymer particles,64,65  liposomes,66  viruslike particles,67  or three-dimensional scaffolds.68  A major advantage of this approach is that the vaccine carrier content is protected from possible degradation and shielded from premature undesired receptor interaction, such as nucleic acids with scavenger receptors.69,70  In Figure 1, we provide an overview of potential vaccine carriers to facilitate codelivery strategies and illustrate their advantages and possible disadvantages. We regard polymers, such as the widely applied poly(lactic-co-glycolic) acid (PLGA), as a good choice for future vaccine formulations. Polymer particles may overcome the general stability issue of liposomes and, in contrast to viruslike particles, constitute nonimmunogenic vehicles, which would allow for possible prime-boost regimens. If biodegradable, polymer particles will gradually release their content over time (days to weeks).

Figure 1

Pros and cons of antigen and adjuvant codelivery vehicles. Arguments for and against the use of various carrier vehicles for (targeted) codelivery of multiple vaccine components.

Figure 1

Pros and cons of antigen and adjuvant codelivery vehicles. Arguments for and against the use of various carrier vehicles for (targeted) codelivery of multiple vaccine components.

Close modal

Improved antigen processing and presentation as a result of colocalization of antigen and stimulus in the same phagosome can explain why codelivering antigen and adjuvant improves T-cell responses.71  At the same time, this approach ensures activation of the cells that have seen the antigen, which is crucial for efficient CD8+ T-cell priming.72 

Targeting of antigen to specific DC subsets reduces the required antigen dose substantially and therefore proved an attractive model for the priming of strong T-cell responses.58  Hence, it appears logical to combine the targeting and codelivery strategies to provide specifically the cell of choice with both antigen and adjuvant. In this way, vaccines become concentrated in APCs specialized for antigen (cross-) presentation and T-cell priming, which, as a consequence, could further reduce the overall vaccine dose. Conversely, several studies suggest that multiple DC subsets are required to induce optimal T-cell immunity.73,74  These and other studies also describe a dependency on type I IFN in raising efficient immune responses, which can be produced by various cell types such as pDCs, myeloid DCs, monocytes, or stromal cells.75-78  Together with the controversy over which DC subset may or may not present the best target, this argues against targeting vaccines to single APC subsets and justifies the question: “Targeting DCs—why bother?”

Targeted codelivery of antigen and adjuvant reduces the risk of adverse reactions

Major arguments in favor of cotargeting antigen and adjuvant lie in a more controlled vaccine application and in a reduced risk of adverse reactions, such as autoimmune responses, induction of tolerance, or unwanted systemic cytokine release (Figure 2). Depending on the frequency and route of vaccine administration, nonphagocytic tissue cells can become overstimulated when exposed to vaccine adjuvants such as TLR agonists. These overstimulated tissue cells may respond with unduly cytokine release, resulting in organ destruction.79,80  Upon intradermal vaccine administration, not only APCs could become activated by TLR agonists, but also keratinocytes, endothelial and mast cells, and fibroblasts or adipocytes, all of which were shown to express TLRs.81  Furthermore, activation of APCs through TLR stimuli in the absence of sufficient antigen could result in the induction of autoimmune responses against the self-antigens presented.82  Indeed, autoimmunity that is dormant, or which has a weak phenotype, can worsen upon stimulation with TLR agonists. This is exemplified by superficial basal cell carcinoma patients experiencing flares of previously well-controlled psoriasis upon treatment with imiquimod (R837) cream.83,84  Thus, their potential to break tolerance, which is so valuable for antitumor therapy, makes TLR agonists at the same time a potentially dangerous means. We believe it is important to administer these powerful agents in a controlled manner. The fact that classical vaccines consisting of pathogen material generally do not cause major health issues may be associated with their local administration. Even more defined adjuvants are not allowed for systemic use, such as the synthetic TLR7 agonist R837 that is currently only approved for topical use in humans, limiting its full potential. Furthermore, separate delivery of antigen and adjuvant may also result in tolerance. This is difficult to substantiate because most vaccine trials merely evaluate whether a vaccine induces the desired humoral or cellular response, not whether tolerance is induced. Adverse reactions to passive targeting using particulate vaccine carriers are unlikely (Figure 2). Here the concomitant uptake of antigen and adjuvant caused by a defined shape and size is naturally restricted to APCs. However, much less antigen will be taken up by the cell of choice compared with the actively targeted approach.

Figure 2

Stochastic visualization of antigen and TLR-L uptake for different vaccine-targeting approaches. The distribution of antigen and TLR-L is based on (A) their physical linkage, (B) their targeting moiety, and (C) their exposure to cells in the various tissues. Depending on the route of vaccine administration, nonphagocytic tissue cells expressing TLRs may become activated.

Figure 2

Stochastic visualization of antigen and TLR-L uptake for different vaccine-targeting approaches. The distribution of antigen and TLR-L is based on (A) their physical linkage, (B) their targeting moiety, and (C) their exposure to cells in the various tissues. Depending on the route of vaccine administration, nonphagocytic tissue cells expressing TLRs may become activated.

Close modal

Potential targeting strategies: from passive to active targeting

Viruses are known to induce strong cytotoxic T-cell responses in the host and may map the way for successful vaccination strategies. Because the sizes of most viruses span a range from 10 to 300 nm, a possible vaccine mimetic should preferentially fall within this range. Interestingly, this is also the size that allows for lymphatic drainage, whereas larger compounds have to be actively transported to the lymph nodes by peripheral DCs.6,85,86  Whether passive or active transport is favorable also depends on which DC subsets are to be targeted, bearing in mind that a combination of both would allow reaching several subsets and possible collaboration to achieve optimal and prolonged immune responses. This also highlights the importance of the route of vaccine administration: subcutaneous injections allow for size-dependent direct drainage through the lymph; intradermal vaccine administration also relies on active transport by skin DCs to the draining lymph nodes. A less invasive method of applying vaccines into the dermis is currently being investigated in the form of (nano) patches that contain dissolving microneedles.87  The intradermal as well as the classic intramuscular vaccine routes also result in a prolonged vaccine supply and consequently a sustained priming period. Interestingly, some light was recently shed on the poorly studied presence of DC subsets in skeletal muscles, describing subsets of moDCs and both CD8α+ and CD11b+ conventional DCs, which migrate after the uptake of antigen and activation to local lymph nodes.88 Intranasal vaccine application reaches pulmonary or lung DCs, and consequently the respective draining lymph nodes. Here the CD11b– CD103+ DCs were ascribed a major role in the uptake of particulates from the airways and their presentation to CD8+ T cells.89,90  This route bears significant potential for a universal vaccine application, because inhalation of dry-powder vaccines is less invasive and overcomes the need for trained medical practitioners and cold storage problems in less developed countries. Intravenous vaccine administration results in the capture by many tissue-resident DCs in the spleen and lymph nodes but may require shielding or targeted approaches if potent immune modulators are used.91  Another way of reaching these cells is direct vaccine application into the lymph nodes (intranodal), where combined administration of antigen and slow polyI:C-releasing microparticles was shown to induce high frequencies of antigen-specific T cells.92  Unequivocally, the choice for a specific route of administration and vaccine carrier are closely intertwined and together determine how effective the passive targeting strategy will be.

Active receptor-dependent targeting of antigen and adjuvant takes vaccine targeting a step further and has recently been investigated. Although direct antibody-antigen-adjuvant conjugates proved protective in a tumor mouse model, further studies of these conjugates revealed preferential uptake mediated via the exposed antigen peptide and its CpG nucleic acid adjuvant moieties over the antibody-binding specificity.93  A refinement of this concept in which antigen and adjuvant are shielded from possible interactions to ensure specific vaccine delivery could be achieved by using vaccine carriers including viruslike particles, liposomes, and polymer particles. The principle of cotargeting antigen and adjuvant is also applicable for gene therapy and might result in a renaissance of this field. For example, Hangalapura and coworkers targeted tumor-antigen–bearing adenovirus to CD40. Although CD40 expression is not restricted to DCs, its ligation results in activation of this cell, thereby improving the antigen-specific CD8+ T-cell response in a mouse melanoma model.94  Lentiviruses are also explored as vehicles for DC targeting in vivo. Lentiviral vectors with Sendbis virus glycoprotein as a ligand for DC-SIGN induce both humoral and cellular responses as well as protection in a mouse tumor model. The absence of adjuvant in this approach argues for an intrinsic stimulatory potential of this vector.95  Nonviral approaches, such as the use of targeted liposomes by van Broekhoven et al and our use of antibody-coated polymer-based nanoparticles,91,96  can overcome the uncertainties of viral strategies. Although the former study lacks a comparison of targeted vs systemic adjuvant application, we showed that the dose of TLR agonists could be reduced 100-fold upon targeting. Importantly, undesired adjuvant effects, such as high blood cytokine levels and hypothermia, were also reduced in the low-dose targeted approach without compromising vaccine efficacy.

Although passive targeting by altering factors such as size and administration route can influence vaccine distribution to some extent, for higher specificity, vaccines must bear targeting molecules, enabling cell type–specific receptor binding. Actively targeted vaccines cannot only induce potent humoral and cellular responses at reduced antigen and adjuvant dosage, but also allow in combination with shielding strategies the use of highly potent immune modulators by avoiding the risk of adverse effects, even when applied systemically (see also Figure 3).

Figure 3

Pros and cons of cotargeting antigen and adjuvant to dendritic cells. Arguments for and against the concept of cotargeting antigen and adjuvant to particular dendritic cell subsets.

Figure 3

Pros and cons of cotargeting antigen and adjuvant to dendritic cells. Arguments for and against the concept of cotargeting antigen and adjuvant to particular dendritic cell subsets.

Close modal

Vaccination is by far the greatest success within the field of immunology to date. Current immunotherapeutic approaches seek to continue this success story to treat chronic infection, cancer, and autoimmune disease by refining the classic vaccine approach. One clear trend is the substitution of actual pathogenic material with synthetic mimetics, with TLR-Ls being a good example in this respect. A second development is the shift toward more complex, but highly controlled, vaccine design. A broad spectrum of vaccine carriers harboring multiple components is being evaluated to increase vaccine efficacy and unravel the underlying immunologic mechanisms, while further control over the induced responses is gained by the addition of targeting moieties. Targeted strategies currently focus mainly on distinct APC subsets. In the near future, these could be mixed and matched to trigger different players of the immune system and to fine-tune the desired immune or tolerogenic responses (Figure 4). We envisage that the immunologist’s toolbox, which consists of submicron-sized targeted carriers harboring both antigen and immunomodulators, will teach us how various subsets may be reached and properly activated. At present, the development of complex vaccine carriers targeted to multiple receptors seems an extremely costly pharmaceutical nightmare. Therefore, in humans, passive vaccine targeting, by modulation of vaccine carrier size and shape or route of administration, or actively targeting a single receptor shared by several cell types, might at this stage represent the most promising strategy. We nevertheless feel that further development of the immunologist’s toolbox is essential to unravel the complexity of immune cell cross-talk and anticipate combinations of targeted approaches, which will ultimately allow full exploitation of the immune system for vaccination purposes.

Figure 4

Fine-tuning vaccine formulations to tailor immune responses to diseases. Vehicle preparation from a choice of antigen, adjuvant, and targeting moieties, such as antibodies, results in versatile vaccine formulations. The combination of different vehicles in one vaccine allows not only for a controlled provision of antigen and adjuvant to the targeted cell subsets, but also for tailoring of Th1, Th2, and type I interferon responses to meet the needs for treatment of specific diseases.

Figure 4

Fine-tuning vaccine formulations to tailor immune responses to diseases. Vehicle preparation from a choice of antigen, adjuvant, and targeting moieties, such as antibodies, results in versatile vaccine formulations. The combination of different vehicles in one vaccine allows not only for a controlled provision of antigen and adjuvant to the targeted cell subsets, but also for tailoring of Th1, Th2, and type I interferon responses to meet the needs for treatment of specific diseases.

Close modal

This work was supported by grants from the EU (ERC advanced PATHFINDER 269019) and the Dutch Cancer Society (KUN2009-4402), as well as a grant from the Dutch government to the Netherlands Institute for Regenerative Medicine (NIRM, grant No. FES0908).

C.F. received the NWO Spinoza award.

Contribution: M.K. prepared the initial draft of the manuscript. P.J.T. and C.G.F. provided further knowledge, insights, and discussions, and helped in critical review. All authors were involved in the design of the manuscript and approved the final version.

Conflict-of-interest disclosure: The authors declare no competing financial interests.

Correspondence: Carl G. Figdor, Department of Tumor Immunology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Center, Geert Grooteplein 26-28, 6525GA Nijmegen, the Netherlands; e-mail: [email protected]

1
Lombard
 
M
Pastoret
 
PP
Moulin
 
AM
 
A brief history of vaccines and vaccination. Rev Sci Tech. 2007;26(1):29-48
2
Jenner
 
E
An Inquiry into the Causes and Effects of the Variolæ Vaccinæ
1798
London
Sampson Low
3
Ramon
 
G
Sur l’augmentation anormale de l’antitoxine chez les chevaux producteurs de serum antidipherique.
Bull Soc Cent Med Vet
1925
, vol. 
101
 (pg. 
227
-
234
)
4
Glenny
 
AT
Pope
 
CG
Waddington
 
H
, et al. 
Immunological notes XVLL.-XXIV.
J Pathol Bacteriol
1926
, vol. 
29
 
1
(pg. 
31
-
40
)
5
Mbow
 
ML
De Gregorio
 
E
Ulmer
 
JB
 
Alum’s adjuvant action: grease is the word. Nat Med. 2011;17(4):415-416
6
Bachmann
 
MF
Jennings
 
GT
 
Vaccine delivery: a matter of size, geometry, kinetics and molecular patterns. Nat Rev Immunol. 2010;10(11):787-796
7
Kantoff
 
PW
Higano
 
CS
Shore
 
ND
, et al. 
 
Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363(5):411-422
8
Morse
 
MA
Chapman
 
R
Powderly
 
J
, et al. 
 
Phase I study utilizing a novel antigen-presenting cell-targeted vaccine with toll-like receptor stimulation to induce immunity to self-antigens in cancer patients. Clin Cancer Res. 2011;17(14):4844-4853
9
Ueno
 
H
Klechevsky
 
E
Schmitt
 
N
, et al. 
 
Targeting human dendritic cell subsets for improved vaccines. Semin Immunol. 2011;23(1):21-27
10
Reis e Sousa
 
C
Dendritic cells in a mature age.
Nat Rev Immunol
2006
, vol. 
6
 
6
(pg. 
476
-
483
)
11
Figdor
 
CG
van Kooyk
 
Y
Adema
 
GJ
 
C-type lectin receptors on dendritic cells and Langerhans cells. Nat Rev Immunol. 2002;2(2):77-84
12
Carayanniotis
 
G
Barber
 
BH
 
Adjuvant-free IgG responses induced with antigen coupled to antibodies against class II MHC. Nature. 1987;327(6117):59-61
13
Snider
 
DP
Kaubisch
 
A
Segal
 
DM
 
Enhanced antigen immunogenicity induced by bispecific antibodies. J Exp Med. 1990;171(6):1957-1963
14
Mahnke
 
K
Guo
 
M
Lee
 
S
, et al. 
 
The dendritic cell receptor for endocytosis, DEC-205, can recycle and enhance antigen presentation via major histocompatibility complex class II-positive lysosomal compartments. J Cell Biol. 2000;151(3):673-684
15
Hawiger
 
D
Inaba
 
K
Dorsett
 
Y
, et al. 
 
Dendritic cells induce peripheral T cell unresponsiveness under steady state conditions in vivo. J Exp Med. 2001;194(6):769-779
16
Bonifaz
 
LC
Bonnyay
 
DP
Charalambous
 
A
, et al. 
In vivo targeting of antigens to maturing dendritic cells via the DEC-205 receptor improves T cell vaccination.
J Exp Med
2004
, vol. 
199
 
6
(pg. 
815
-
824
)
17
He
 
LZ
Crocker
 
A
Lee
 
J
, et al. 
 
Antigenic targeting of the human mannose receptor induces tumor immunity. J Immunol. 2007;178(10):6259-6267
18
Carter
 
RW
Thompson
 
C
Reid
 
DM
Wong
 
SY
Tough
 
DF
 
Preferential induction of CD4+ T cell responses through in vivo targeting of antigen to dendritic cell-associated C-type lectin-1. J Immunol. 2006;177(4):2276-2284
19
Freire
 
T
Zhang
 
X
Deriaud
 
E
, et al. 
 
Glycosidic Tn-based vaccines targeting dermal dendritic cells favor germinal center B-cell development and potent antibody response in the absence of adjuvant. Blood. 2010;116(18):3526-3536
20
Tacken
 
PJ
Joosten
 
B
Reddy
 
A
, et al. 
 
No advantage of cell-penetrating peptides over receptor-specific antibodies in targeting antigen to human dendritic cells for cross-presentation. J Immunol. 2008;180(11):7687-7696
21
Meyer-Wentrup
 
F
Benitez-Ribas
 
D
Tacken
 
PJ
, et al. 
 
Targeting DCIR on human plasmacytoid dendritic cells results in antigen presentation and inhibits IFN-alpha production. Blood. 2008;111(8):4245-4253
22
Sancho
 
D
Joffre
 
OP
Keller
 
AM
, et al. 
Identification of a dendritic cell receptor that couples sensing of necrosis to immunity.
Nature
2009
, vol. 
458
 
7240
(pg. 
899
-
903
)
23
Zhang
 
JG
Czabotar
 
PE
Policheni
 
AN
, et al. 
 
The dendritic cell receptor Clec9A binds damaged cells via exposed actin filaments. Immunity. 2012;36(4):646-657
24
Ahrens
 
S
Zelenay
 
S
Sancho
 
D
, et al. 
 
F-actin is an evolutionarily conserved damage-associated molecular pattern recognized by DNGR-1, a receptor for dead cells. Immunity. 2012;36(4):635-645
25
Zelenay
 
S
Keller
 
AM
Whitney
 
PG
, et al. 
 
The dendritic cell receptor DNGR-1 controls endocytic handling of necrotic cell antigens to favor cross-priming of CTLs in virus-infected mice. J Clin Invest. 2012;122(5):1615-1627
26
Iborra
 
S
Izquierdo
 
HM
Martinez-Lopez
 
M
Blanco-Menendez
 
N
Reis
 
ESC
Sancho
 
D
 
The DC receptor DNGR-1 mediates cross-priming of CTLs during vaccinia virus infection in mice. J Clin Invest. 2012;122(5):1628-1643
27
Shortman
 
K
Heath
 
WR
 
The CD8+ dendritic cell subset. Immunol Rev. 2010;234(1):18-31
28
Loschko
 
J
Schlitzer
 
A
Dudziak
 
D
, et al. 
 
Antigen delivery to plasmacytoid dendritic cells via BST2 induces protective T cell-mediated immunity. J Immunol. 2011;186(12):6718-6725
29
Loschko
 
J
Heink
 
S
Hackl
 
D
, et al. 
 
Antigen targeting to plasmacytoid dendritic cells via Siglec-H inhibits Th cell-dependent autoimmunity. J Immunol. 2011. E-pub November 14, 2011 DOI jimmunol.1102307 [pii]
30
Zhang
 
J
Raper
 
A
Sugita
 
N
, et al. 
 
Characterization of Siglec-H as a novel endocytic receptor expressed on murine plasmacytoid dendritic cell precursors. Blood. 2006;107(9):3600-3608
31
Colonna
 
M
Krug
 
A
Cella
 
M
 
Interferon-producing cells: on the front line in immune responses against pathogens. Curr Opin Immunol. 2002;14(3):373-379
32
Cheong
 
C
Matos
 
I
Choi
 
JH
, et al. 
 
Microbial stimulation fully differentiates monocytes to DC-SIGN/CD209(+) dendritic cells for immune T cell areas. Cell. 2010;143(3):416-429
33
Schliehe
 
C
Redaelli
 
C
Engelhardt
 
S
, et al. 
 
CD8- dendritic cells and macrophages cross-present poly(D,L-lactate-co-glycolate) acid microsphere-encapsulated antigen in vivo. J Immunol. 2011;187(5):2112-2121
34
Sancho
 
D
Mourão-Sá
 
D
Joffre
 
OP
, et al. 
 
Tumor therapy in mice via antigen targeting to a novel, DC-restricted C-type lectin. J Clin Invest. 2008;118(6):2098-2110
35
Galibert
 
L
Diemer
 
GS
Liu
 
Z
, et al. 
 
Nectin-like protein 2 defines a subset of T-cell zone dendritic cells and is a ligand for class-I-restricted T-cell-associated molecule. J Biol Chem. 2005;280(23):21955-21964
36
Robbins
 
SH
Walzer
 
T
Dembele
 
D
, et al. 
 
Novel insights into the relationships between dendritic cell subsets in human and mouse revealed by genome-wide expression profiling. Genome Biol. 2008;9(1):R17
37
Caminschi
 
I
Proietto
 
AI
Ahmet
 
F
, et al. 
 
The dendritic cell subtype-restricted C-type lectin Clec9A is a target for vaccine enhancement. Blood. 2008;112(8):3264-3273
38
Huysamen
 
C
Willment
 
JA
Dennehy
 
KM
Brown
 
GD
 
CLEC9A is a novel activation C-type lectin-like receptor expressed on BDCA3+ dendritic cells and a subset of monocytes. J Biol Chem. 2008;283(24):16693-16701
39
Bachem
 
A
Güttler
 
S
Hartung
 
E
, et al. 
Superior antigen cross-presentation and XCR1 expression define human CD11c+CD141+ cells as homologues of mouse CD8+ dendritic cells.
J Exp Med
2010
, vol. 
207
 
6
(pg. 
1273
-
1281
)
40
Crozat
 
K
Guiton
 
R
Contreras
 
V
, et al. 
The XC chemokine receptor 1 is a conserved selective marker of mammalian cells homologous to mouse CD8alpha+ dendritic cells.
J Exp Med
2010
, vol. 
207
 
6
(pg. 
1283
-
1292
)
41
Jongbloed
 
SL
Kassianos
 
AJ
McDonald
 
KJ
, et al. 
 
Human CD141+ (BDCA-3)+ dendritic cells (DCs) represent a unique myeloid DC subset that cross-presents necrotic cell antigens. J Exp Med. 2010;207(6):1247-1260
42
Poulin
 
LF
Salio
 
M
Griessinger
 
E
, et al. 
 
Characterization of human DNGR-1+ BDCA3+ leukocytes as putative equivalents of mouse CD8alpha+ dendritic cells. J Exp Med. 2010;207(6):1261-1271
43
Villadangos
 
JA
Shortman
 
K
 
Found in translation: the human equivalent of mouse CD8+ dendritic cells. J Exp Med. 2010;207(6):1131-1134
44
Schreibelt
 
G
Klinkenberg
 
LJ
Cruz
 
LJ
, et al. 
 
The C type lectin receptor CLEC9A mediates antigen uptake and (cross-)presentation by human blood BDCA3+ myeloid dendritic cells. Blood. 2012;119(10):2284-2292
45
Mittag
 
D
Proietto
 
AI
Loudovaris
 
T
, et al. 
 
Human dendritic cell subsets from spleen and blood are similar in phenotype and function but modified by donor health status. J Immunol. 2011;186(11):6207-6217
46
Haniffa
 
M
Shin
 
A
Bigley
 
V
, et al. 
 
Human tissues contain CD141(hi) cross-presenting dendritic cells with functional homology to mouse CD103(+) nonlymphoid dendritic cells. Immunity. 2012;37(1):60-73
47
Chu
 
CC
Ali
 
N
Karagiannis
 
P
, et al. 
 
Resident CD141 (BDCA3)+ dendritic cells in human skin produce IL-10 and induce regulatory T cells that suppress skin inflammation. J Exp Med. 2012;209(5):935-945
48
Hoeffel
 
G
Ripoche
 
AC
Matheoud
 
D
, et al. 
 
Antigen crosspresentation by human plasmacytoid dendritic cells. Immunity. 2007;27(3):481-492
49
Di Pucchio
 
T
Chatterjee
 
B
Smed-Sorensen
 
A
, et al. 
 
Direct proteasome-independent cross-presentation of viral antigen by plasmacytoid dendritic cells on major histocompatibility complex class I. Nat Immunol. 2008;9(5):551-557
50
Tel
 
J
Lambeck
 
AJ
Cruz
 
LJ
Tacken
 
PJ
de Vries
 
IJ
Figdor
 
CG
 
Human plasmacytoid dendritic cells phagocytose, process, and present exogenous particulate antigen. J Immunol. 2010;184(8):4276-4283
51
van de Ven
 
R
van den Hout
 
MF
Lindenberg
 
JJ
, et al. 
 
Characterization of four conventional dendritic cell subsets in human skin-draining lymph nodes in relation to T-cell activation. Blood. 2011;118(9):2502-2510
52
Alexopoulou
 
L
Holt
 
AC
Medzhitov
 
R
Flavell
 
RA
 
Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3. Nature. 2001;413(6857):732-738
53
Diebold
 
SS
Massacrier
 
C
Akira
 
S
, et al. 
Nucleic acid agonists for Toll-like receptor 7 are defined by the presence of uridine ribonucleotides.
Eur J Immunol
2006
, vol. 
36
 
12
(pg. 
3256
-
3267
)
54
Jurk
 
M
Heil
 
F
Vollmer
 
J
, et al. 
 
Human TLR7 or TLR8 independently confer responsiveness to the antiviral compound R-848. Nat Immunol. 2002;3(6):499
55
Hemmi
 
H
Kaisho
 
T
Takeuchi
 
O
, et al. 
 
Small anti-viral compounds activate immune cells via the TLR7 MyD88-dependent signaling pathway. Nat Immunol. 2002;3(2):196-200
56
Klinman
 
DM
Klaschik
 
S
Sato
 
T
Tross
 
D
 
CpG oligonucleotides as adjuvants for vaccines targeting infectious diseases. Adv Drug Deliv Rev. 2009;61(3):248-255
57
Krieg
 
AM
Yi
 
AK
Matson
 
S
, et al. 
 
CpG motifs in bacterial DNA trigger direct B-cell activation. Nature. 1995;374(6522):546-549
58
Bonifaz
 
L
Bonnyay
 
D
Mahnke
 
K
, et al. 
Efficient targeting of protein antigen to the dendritic cell receptor DEC-205 in the steady state leads to antigen presentation on major histocompatibility complex class I products and peripheral CD8+ T cell tolerance.
J Exp Med
2002
, vol. 
196
 
12
(pg. 
1627
-
1638
)
59
Li
 
D
Romain
 
G
Flamar
 
AL
, et al. 
 
Targeting self- and foreign antigens to dendritic cells via DC-ASGPR generates IL-10-producing suppressive CD4+ T cells. J Exp Med. 2012;209(1):109-121
60
Idoyaga
 
J
Lubkin
 
A
Fiorese
 
C
, et al. 
 
Comparable T helper 1 (Th1) and CD8 T-cell immunity by targeting HIV gag p24 to CD8 dendritic cells within antibodies to Langerin, DEC205, and Clec9A. Proc Natl Acad Sci U S A. 2011;108(6):2384-2389
61
Kasturi
 
SP
Skountzou
 
I
Albrecht
 
RA
, et al. 
Programming the magnitude and persistence of antibody responses with innate immunity.
Nature
2011
, vol. 
470
 
7335
(pg. 
543
-
547
)
62
Maurer
 
T
Heit
 
A
Hochrein
 
H
, et al. 
CpG-DNA aided cross-presentation of soluble antigens by dendritic cells.
Eur J Immunol
2002
, vol. 
32
 
8
(pg. 
2356
-
2364
)
63
Cho
 
HJ
Takabayashi
 
K
Cheng
 
PM
, et al. 
Immunostimulatory DNA-based vaccines induce cytotoxic lymphocyte activity by a T-helper cell-independent mechanism.
Nat Biotechnol
2000
, vol. 
18
 
5
(pg. 
509
-
514
)
64
Cruz
 
LJ
Tacken
 
PJ
Fokkink
 
R
, et al. 
Targeted PLGA nano- but not microparticles specifically deliver antigen to human dendritic cells via DC-SIGN in vitro.
J Control Release
2010
, vol. 
144
 
2
(pg. 
118
-
126
)
65
Zhang
 
Z
Tongchusak
 
S
Mizukami
 
Y
, et al. 
Induction of anti-tumor cytotoxic T cell responses through PLGA-nanoparticle mediated antigen delivery.
Biomaterials
2011
, vol. 
32
 
14
(pg. 
3666
-
3678
)
66
Thomann
 
JS
Heurtault
 
B
Weidner
 
S
, et al. 
 
Antitumor activity of liposomal ErbB2/HER2 epitope peptide-based vaccine constructs incorporating TLR agonists and mannose receptor targeting. Biomaterials. 2011;32(20):4574-4583
67
Speiser
 
DE
Schwarz
 
K
Baumgaertner
 
P
, et al. 
 
Memory and effector CD8 T-cell responses after nanoparticle vaccination of melanoma patients. J Immunother. 2010;33(8):848-858
68
Ali
 
OA
Emerich
 
D
Dranoff
 
G
Mooney
 
DJ
 
In situ regulation of DC subsets and T cells mediates tumor regression in mice. Sci Transl Med. 2009;1(8):8ra19
69
Kimura
 
Y
Sonehara
 
K
Kuramoto
 
E
, et al. 
 
Binding of oligoguanylate to scavenger receptors is required for oligonucleotides to augment NK cell activity and induce IFN. J Biochem. 1994;116(5):991-994
70
Zhu
 
FG
Reich
 
CF
Pisetsky
 
DS
 
The role of the macrophage scavenger receptor in immune stimulation by bacterial DNA and synthetic oligonucleotides. Immunology. 2001;103(2):226-234
71
Blander
 
JM
Medzhitov
 
R
Toll-dependent selection of microbial antigens for presentation by dendritic cells.
Nature
2006
, vol. 
440
 
7085
(pg. 
808
-
812
)
72
Kratky
 
W
Reis
 
ESC
Oxenius
 
A
Sporri
 
R
 
Direct activation of antigen-presenting cells is required for CD8+ T-cell priming and tumor vaccination. Proc Natl Acad Sci U S A. 2011;108(42):17414-17419
73
Kastenmuller
 
K
Wille-Reece
 
U
Lindsay
 
RW
, et al. 
 
Protective T cell immunity in mice following protein-TLR7/8 agonist-conjugate immunization requires aggregation, type I IFN, and multiple DC subsets. J Clin Invest. 2011;121(5):1782-1796
74
Oh
 
JZ
Kurche
 
JS
Burchill
 
MA
Kedl
 
RM
 
TLR7 enables cross-presentation by multiple dendritic cell subsets through a type I IFN-dependent pathway. Blood. 2011;118(11):3028-3038
75
Fuertes
 
MB
Kacha
 
AK
Kline
 
J
, et al. 
 
Host type I IFN signals are required for antitumor CD8+ T cell responses through CD8{alpha}+ dendritic cells. J Exp Med. 2011;208(10):2005-2016
76
McCartney
 
SA
Vermi
 
W
Lonardi
 
S
, et al. 
 
RNA sensor-induced type I IFN prevents diabetes caused by a beta cell-tropic virus in mice. J Clin Invest. 2011;121(4):1497-1507
77
Piccioli
 
D
Sammicheli
 
C
Tavarini
 
S
, et al. 
 
Human plasmacytoid dendritic cells are unresponsive to bacterial stimulation and require a novel type of cooperation with myeloid dendritic cells for maturation. Blood. 2009;113(18):4232-4239
78
Longhi
 
MP
Trumpfheller
 
C
Idoyaga
 
J
, et al. 
 
Dendritic cells require a systemic type I interferon response to mature and induce CD4+ Th1 immunity with poly IC as adjuvant. J Exp Med. 2009;206(7):1589-1602
79
Bourquin
 
C
Anz
 
D
Zwiorek
 
K
, et al. 
 
Targeting CpG oligonucleotides to the lymph node by nanoparticles elicits efficient antitumoral immunity. J Immunol. 2008;181(5):2990-2998
80
Storni
 
T
Ruedl
 
C
Schwarz
 
K
Schwendener
 
RA
Renner
 
WA
Bachmann
 
MF
 
Nonmethylated CG motifs packaged into virus-like particles induce protective cytotoxic T cell responses in the absence of systemic side effects. J Immunol. 2004;172(3):1777-1785
81
Miller
 
LS
Modlin
 
RL
 
Toll-like receptors in the skin. Semin Immunopathol. 2007;29(1):15-26
82
Mills
 
KH
 
TLR-dependent T cell activation in autoimmunity. Nat Rev Immunol. 2011;11(12):807-822
83
Wu
 
JK
Siller
 
G
Strutton
 
G
 
Psoriasis induced by topical imiquimod. Australas J Dermatol. 2004;45(1):47-50
84
Rajan
 
N
Langtry
 
JA
 
Generalized exacerbation of psoriasis associated with imiquimod cream treatment of superficial basal cell carcinomas. Clin Exp Dermatol. 2006;31(1):140-141
85
Reddy
 
ST
van der Vlies
 
AJ
Simeoni
 
E
, et al. 
 
Exploiting lymphatic transport and complement activation in nanoparticle vaccines. Nat Biotechnol. 2007;25(10):1159-1164
86
Manolova
 
V
Flace
 
A
Bauer
 
M
Schwarz
 
K
Saudan
 
P
Bachmann
 
MF
 
Nanoparticles target distinct dendritic cell populations according to their size. Eur J Immunol. 2008;38(5):1404-1413
87
Raphael
 
AP
Prow
 
TW
Crichton
 
ML
Chen
 
X
Fernando
 
GJ
Kendall
 
MA
 
Targeted, needle-free vaccinations in skin using multilayered, densely-packed dissolving microprojection arrays. Small. 2010;6(16):1785-1793
88
Langlet
 
C
Tamoutounour
 
S
Henri
 
S
, et al. 
 
CD64 expression distinguishes monocyte-derived and conventional dendritic cells and reveals their distinct role during intramuscular immunization. J Immunol. 2012;188(4):1751-1760
89
Jakubzick
 
C
Helft
 
J
Kaplan
 
TJ
Randolph
 
GJ
 
Optimization of methods to study pulmonary dendritic cell migration reveals distinct capacities of DC subsets to acquire soluble versus particulate antigen. J Immunol Methods. 2008;337(2):121-131
90
Nembrini
 
C
Stano
 
A
Dane
 
KY
, et al. 
 
Nanoparticle conjugation of antigen enhances cytotoxic T-cell responses in pulmonary vaccination. Proc Natl Acad Sci U S A. 2011;108(44):E989-E997
91
Tacken
 
PJ
Zeelenberg
 
IS
Cruz
 
LJ
, et al. 
 
Targeted delivery of Toll-like receptor ligands to human and mouse dendritic cells strongly enhances adjuvanticity. Blood. 2011;118(26):6836-6844
92
Jewell
 
CM
Bustamante Lopez
 
SC
Irvine
 
DJ
 
In situ engineering of the lymph node microenvironment via intranodal injection of adjuvant-releasing polymer particles. Proc Natl Acad Sci U S A. 2011;108(38):15745-15750
93
Kreutz
 
M
Giquel
 
B
Hu
 
Q
, et al. 
 
Antibody-antigen-adjuvant conjugates enable co-delivery of antigen and adjuvant to dendritic cells in cis but only have partial targeting specificity. PLoS One. 2012;7(7):e40208
94
Yang
 
L
Yang
 
H
Rideout
 
K
, et al. 
 
Engineered lentivector targeting of dendritic cells for in vivo immunization. Nat Biotechnol. 2008;26(3):326-334
95
Hangalapura BN, Oosterhoff D, de Groot J, et al. Potent antitumor immunity generated by a CD40-targeted adenoviral vaccine. Cancer Res. 2011;71(17):5827-5837
96
van Broekhoven
 
CL
Parish
 
CR
Demangel
 
C
Britton
 
WJ
Altin
 
JG
 
Targeting dendritic cells with antigen-containing liposomes: a highly effective procedure for induction of antitumor immunity and for tumor immunotherapy. Cancer Res. 2004;64(12):4357-4365
97
Bennett
 
CL
Fallah-Arani
 
F
Conlan
 
T
, et al. 
 
Langerhans cells regulate cutaneous injury by licensing CD8 effector cells recruited to the skin. Blood. 2011;117(26):7063-7069
98
King
 
IL
Kroenke
 
MA
Segal
 
BM
 
GM-CSF-dependent, CD103+ dermal dendritic cells play a critical role in Th effector cell differentiation after subcutaneous immunization. J Exp Med. 2010;207(5):953-961
99
Kretz-Rommel
 
A
Qin
 
F
Dakappagari
 
N
, et al. 
 
In vivo targeting of antigens to human dendritic cells through DC-SIGN elicits stimulatory immune responses and inhibits tumor growth in grafted mouse models. J Immunother. 2007;30(7):715-726
100
Joffre
 
OP
Sancho
 
D
Zelenay
 
S
Keller
 
AM
Reis e Sousa
 
C
 
Efficient and versatile manipulation of the peripheral CD4+ T-cell compartment by antigen targeting to DNGR-1/CLEC9A. Eur J Immunol. 2010;40(5):1255-1265
101
Singh
 
SK
Stephani
 
J
Schaefer
 
M
, et al. 
 
Targeting glycan modified OVA to murine DC-SIGN transgenic dendritic cells enhances MHC class I and II presentation. Mol Immunol. 2009;47(2-3):164-174
102
Bozzacco
 
L
Trumpfheller
 
C
Siegal
 
FP
, et al. 
DEC-205 receptor on dendritic cells mediates presentation of HIV gag protein to CD8+ T cells in a spectrum of human MHC I haplotypes.
Proc Natl Acad Sci USA
2007
, vol. 
104
 
4
(pg. 
1289
-
1294
)
103
Ramakrishna
 
V
Vasilakos
 
JP
Tario
 
JD
Berger
 
MA
Wallace
 
PK
Keler
 
T
 
Toll-like receptor activation enhances cell-mediated immunity induced by an antibody vaccine targeting human dendritic cells. J Transl Med. 2007;5:5
104
Klechevsky
 
E
Morita
 
R
Liu
 
M
, et al. 
 
Functional specializations of human epidermal Langerhans cells and CD14+ dermal dendritic cells. Immunity. 2008;29(3):497-510
105
Apostolopoulos
 
V
Pietersz
 
GA
Tsibanis
 
A
, et al. 
 
Pilot phase III immunotherapy study in early-stage breast cancer patients using oxidized mannan-MUC1 [ISRCTN71711835]. Breast Cancer Res. 2006;8(3):R27
106
Kwon
 
YJ
James
 
E
Shastri
 
N
, et al. 
In vivo targeting of dendritic cells for activation of cellular immunity using vaccine carriers based on pH-responsive microparticles.
Proc Natl Acad Sci USA
2005
, vol. 
102
 
51
(pg. 
18264
-
18268
)
107
Joshi
 
MD
Unger
 
WW
van Beelen
 
AJ
, et al. 
 
DC-SIGN mediated antigen-targeting using glycan-modified liposomes: formulation considerations. Int J Pharm. 2011;416(2):426-432
108
Singh
 
SK
Streng-Ouwehand
 
I
Litjens
 
M
, et al. 
 
Design of neo-glycoconjugates that target the mannose receptor and enhance TLR-independent cross-presentation and Th1 polarization. Eur J Immunol. 2011;41(4):916-925
109
Fukasawa
 
M
Shimizu
 
Y
Shikata
 
K
, et al. 
 
Liposome oligomannose-coated with neoglycolipid, a new candidate for a safe adjuvant for induction of CD8+ cytotoxic T lymphocytes. FEBS Lett. 1998;441(3):353-356
110
Badiee
 
A
Davies
 
N
McDonald
 
K
, et al. 
 
Enhanced delivery of immunoliposomes to human dendritic cells by targeting the multilectin receptor DEC-205. Vaccine. 2007;25(25):4757-4766
111
Gieseler
 
RK
Marquitan
 
G
Hahn
 
MJ
, et al. 
 
DC-SIGN-specific liposomal targeting and selective intracellular compound delivery to human myeloid dendritic cells: implications for HIV disease. Scand J Immunol. 2004;59(5):415-424
112
Korokhov
 
N
de Gruijl
 
TD
Aldrich
 
WA
, et al. 
 
High efficiency transduction of dendritic cells by adenoviral vectors targeted to DC-SIGN. Cancer Biol Ther. 2005;4(3):289-294
113
Brandao
 
JG
Scheper
 
RJ
Lougheed
 
SM
, et al. 
 
CD40-targeted adenoviral gene transfer to dendritic cells through the use of a novel bispecific single-chain Fv antibody enhances cytotoxic T cell activation. Vaccine. 2003;21(19-20):2268-2272
114
Belousova
 
N
Korokhov
 
N
Krendelshchikova
 
V
, et al. 
 
Genetically targeted adenovirus vector directed to CD40-expressing cells. J Virol. 2003;77(21):11367-11377
Sign in via your Institution