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Dendritic Cells: Important Adjuvants During DNA Vaccination

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Vaccine design focuses on the identification of safe forms of antigen that elicit protective immunity. Adjuvants are also critical for efficacy, especially for inducing strong T cell-mediated responses. Dendritic cells (DCs) are nature’s adjuvants, specialized to capture and process antigens and exert several costimulatory functions that expand Th1 helper and cytolytic T lymphocytes. Antigen-bearing DCs, in the absence of additional adjuvants, immunize mice to develop antimicrobial and anti- tumor immunity.

This chapter concentrates on the features and mechanisms that allow DCs to control immunity. So-called immature DCs can capture antigens by many routes, including uptake of other cells transfected by a DNA vaccine. Maturing DCs then 1) generate large amounts of MHC-peptide complexes, 2) produce chemokines that recruit other DCs and T cells, 3) reshape their chemokine receptors, e.g., upregulate CCR7, to increase homing and function in lymph nodes, 4) release cytokines like IL-12 that activate natural killer cells and polarize T cells to the protective Th1 phenotype, and 5) express numerous T cell adhesion and costimulatory products. The latter include C-type lectins such as DC-SIGN, several TNF/TNF-R family members such as CD40 and TRANCE-R, and many B7 family molecules such as CD86. By mobilizing DCs in the setting of DNA vaccination, one therefore exploits specialized antigen presenting cells with many mechanisms for enhancing immunity. This adjuvant role has been demonstrated recently in humans who have been vaccinated with autologous, antigen-bearing DCs.

In the context of DNA vaccines, three valuable potentials of DCs are evident. 1) DCs are directly transduced with vaccine DNA, leading to presentation of vaccine antigens on MHC class I and II products. In mice, DCs are the main white blood cells that are directly transfected. Since it is known that T cells are primed to bone marrow derived cells, rather than nonhematopoietic cells, the transfected DCs likely account for the initial immune priming by DNA vaccines. However with current methods, the frequency of transfected DCs is small, and the cells are short-lived. 2) DCs can capture antigens from other cells, presumably including DNA-transfected muscle and skin cells that die during normal cell turnover. The resulting “cross presentation” of cellular antigens may allow DCs to expand and sustain vaccine memory in the CD4 helper and CD8 killer compartments. 3) DCs also respond directly to DNA and to specific CpG oligodeoxynucleotides. This means that DNA vaccines, distinct from their capacity to encode specific antigens, stimulate DCs to mature and become powerful stimulators of T cell immunity. As a corollary, if a DNA vaccine fails to stimulate DC maturation, then the cells might be able to induce different forms of tolerance and suppress immunity. DNA vaccination therefore brings into focus important areas of DC physiology. Reciprocally DC physiology should provide useful guidelines for improving the efficacy of DNA vaccination.

Dendritic Cells as Effective Initiators of T Cell Immunity

When a vaccine is being designed to elicit T cell-mediated immunity, especially Th1 helper cells and cytolytic T lymphocytes (CTL),1 a central challenge is to deliver the vaccine to appropriate antigen presenting cells. In the case of DNA or other vaccines, the expression and delivery of a foreign protein by itself is insufficient. If simple expression of vaccine antigens would suffice to elicit immunity, we might have more candidate HIV-1 vaccines because the genes, proteins, and processed peptides of this virus have been known for some time. In this section, we consider some of the early work that revealed a role for DCs as nature’s adjuvants for initiating T cell immunity. In the next section, we point out that DCs must mature to exert their adjuvant roles, and that maturation is stimulated by select infectious agents and DNA vaccines.

Microbial and Cellular Extracts Are by Themselves Poor Initiators of T Cell-Mediated Immunity

At the time that DCs were discovered in the 1970’s, the standard experimental models of cellular immunity to microbial infection involved mycobacteria and Listeria monocytogenes. Killed bacteria and protein rich microbial extracts would elicit recall immune responses termed delayed type hypersensitivity. Yet these same proteins were insufficient as vaccines.2 Likewise, people who are infected with M.Tuberculosis or the BCG vaccine readily express delayed type hypersensitivity during the PPD skin test. Yet this same skin test does not prime uninfected individuals, even when given on an annual basis for dozens of years. The interpretation, that one needs live organisms to elicit strong immunity, more or less restates the finding but does not explain why foreign antigens alone often are not immunogenic. An analogous situation held true for the most powerful T cell response known, graft rejection. Medawer, who discovered the immune basis of graft rejection, spent years trying to extract active transplantation antigens but without success,3 even though his extracts very likely contained MHC products. In both these infection and transplantation systems, it was not known that strong cell-mediated immunity occurs when antigens are presented on viable DCs. Although it is not yet established that DCs are absolutely essential for the induction of various T cell responses in vivo, it is clear that DCs are effective adjuvants and express several underlying mechanisms to carry out this role.4,5

Antigen Presenting Cells in the Afferent and Efferent Limbs of T-Dependent Immunity in Culture

The starting point for experimentation on DCs was a system for studying primary immune responses to antigen, the Mishell-Dutton culture. In this system, mouse splenocytes formed IgM antibody to sheep red blood cells in a T cell dependent manner. In addition, nonlymphocytic, radioresistant “accessory cells” were needed to elicit the primary response. It was not known what the cells were or how they worked. Nevertheless, Mishell-Dutton cultures were the available model to ask questions about primary immune responses, to determine the requirements for converting a foreign antigen into an immunogen.

An analysis of the accessory cells revealed the presence of a new cell type, the DC, which had to be distinguished from macrophages to be isolated and characterized.68 The DCs were purified on the basis of several distinctive properties such as a paucity of Fc receptors, presence of the 33D1 antigen, and poor adherence to plastic (in each case, using their unusual shape and motility as additional markers).68 Human blood and tonsil also contained comparably distinct DCs.9,10 The identification of DCs did not require the use of antibodies to MHC II products, the alternative means that was being used at that time to identify accessory cells. These antibodies initially were called anti-Ia or anti “I region associated” antibodies, because the I region (later, MHC II) was involved in immune responsiveness. The use of anti-MHC II antibodies in retrospect was a circular way to select active accessory cells, since MHC II later proved to be essential for antigen presentation to CD4 helper T lymphocytes.

After purification as distinct leukocytes, DCs were found to express very high levels of MHC II7,9,10 and to act as remarkably potent stimulators of many different T cell responses. Small numbers of DCs mediated the antibody response to red blood cells and to hapten-carrier conjugates.11,12 Potent direct stimulation of T cells was observed in the responses to carrier proteins12 and to alloantigens in the mixed leukocyte reaction.13 Prior work had used 1:1 ratios of antigen presenting cells to T cells, but enriched DCs were active at 1:100 and even lower ratios. When depleted of DCs, other antigen presenting populations, such as MHC class II positive B cells and macrophages were weak or inactive in initiating immunity in culture. While DCs initiated responses in culture, other antigen presenting cells proved to be critical for the effector limb of immunity. For example, in T-dependent antibody formation, DCs first present antigens to expand and differentiate CD4 helper T cells. Then the activated helper cells respond very efficiently to antigens presented by B cells to bring about antibody formation.12,14 Likewise, DCs activate T cells that induce macrophages in an MHC-restricted fashion to produce inflammatory cytokines.15 DCs also stimulate CD8 T cells in the afferent or first stage of the cytotoxic T cell response, whereupon these T cells kill targets presenting antigen in the efferent limb.16,17 Therefore, many different types of antigen presenting cells work together to generate T cell-dependent immune reactions.

The Costimulatory Properties of Dendritic Cells

In the early days of research on DCs, their capacity to vigorously stimulate T cell growth was noted in many systems in which antigen processing was not required. The systems included the mixed leukocyte reaction to major transplantation antigens,13 and T cell proliferation to mitogens18,19 and later superantigens.20 Therefore DCs were not simply antigen presenting cells, but expressed additional “accessory” functions or if one wishes “second signals” and “costimulatory” effects. This was especially evident in situations where the required T cell stimulus, e.g., a superantigen or anti-CD3 antibody, was estimated to be very small. As few as 100–200 T cell ligands per DC were sufficient to activate polyclonal populations of resting T cells,20,21 again suggesting that DCs had well developed accessory functions. Ironically (below), DCs are proving to have special mechanisms for forming MHC-peptide complexes or “signal one.”

The Potency of DCs in Initiating MHC-Restricted Immunity

An unusual feature of DCs was their potency. Small numbers of DCs resulted in strong T cell growth, CTL differentiation, and lymphokine production. Simultaneously, DCs controlled the MHC restriction of the response. If DCs of MHC-A were used to prime T cells of MHC-B in the afferent limb of the MLR, the activated T cells helped B cells of MHC-A, not MHC-B, to grow and produce antibody in the efferent limb of the response.14 If DCs of MHC-A primed MHC-A helper T cells to the KLH carrier protein, the helpers only triggered antibody responses to a hapten-KLH complex if the lymphocytes were also MHC-A.12 DCs in the afferent limb therefore control the MHC restriction observed in the efferent limb of immunity. Current research on the mechanisms underlying DC function are considered below, after we first discuss DC maturation and the quality of the T cell response induced by DCs.

Dendritic Cell Maturation: A Control Point for Initiating Immunity in Tissue Culture

The studies above indicate that vaccine antigens gain efficacy when presented on DCs. Yet the targeting of proteins or preprocessed peptides to DCs is not enough. DCs also must differentiate or mature into potent stimulators of T cell immunity.

Maturation of Epidermal Langerhans Cells in Culture

After DCs had been described in lymphoid tissues, the sites for generating primary immune responses, it was natural to turn to peripheral tissues, the sites for antigen entry. Skin22 and lung23 were the first examples. In skin, MHC class II rich cells (Langerhans cells) had been shown to be antigen presenting cells for recall responses.24 However in epidermal cell suspensions, typical MHC II positive DCs could only be identified after the cells had undergone a series of major changes in culture. These cultured DCs expressed high levels of surface MHC products and potent T cell stimulatory function, the strongest that had been observed. The term “maturation” was used to describe the terminal differentiation of Langerhans cells to powerful DC stimulators. It was proposed that DC maturation was critical for converting antigens into strong immunogens.22 Similar events were apparent in the lung25 and spleen.26

Antigen Uptake and T Cell Stimulation by Dendritic Cells Can Be Separated in Time

A further surprise came when potent DCs, cultured from skin or spleen, were tested for their capacity to present protein antigens.26,27 Presentation of proteins was actually weak or nondetectable, even though the same cells were potent presenters of alloantigens and preprocessed peptides. Instead, the protein had to be administered when the DCs were immature; otherwise the antigen seemed to be ignored. It later became evident that immature DCs could endocytose antigens by a number of routes: macropinocytosis, phagocytosis, and adsorptive or receptor mediated uptake.2831 Mature DCs in contrast had weak endocytic activity for many soluble tracers and particulates. Some underlying mechanisms are discussed below. Nevertheless, antigen capture and T cell stimulation were separate components of immunogenicity, and DC maturation encompassed both sequentially in time.

Dendritic Cell Maturation Stimuli, Including Select CpG Oligodeoxynucleotides

Maturation occurred “spontaneously” in the initial experiments in cultured mouse epidermis,22 mouse spleen,26,32 and human blood.33 When the immature DCs were purified, cytokine requirements became evident including GM-CSF and other factors in monocyte conditioned media.34,35 Subsequent studies identified a combination of TNFα, IL-1β, and the prostaglandin PGE2 as effective inflammatory mediators of maturation.36,37 CD40L and TRANCE (RANK ligand) are additional, cell-associated, TNF family members that control DC maturation and function.38,39 There likely will be more, including TNF/TNF-R molecules that DCs use to influence other cells. Certain necrotic cells can induce maturation,40,41 possibly through heat shock proteins.42

Importantly, many microbial products stimulate DC maturation in culture, including LPS,43,44 double stranded RNA,45,46 and CpG oligodeoxynucleotide (ODN) sequences.47,48 CpG ODN’s additionally expand the number of mature DCs in lymphoid organs in mice.49 Many receptors for maturation (IL-1R, TNF R like CD40 and CD120, and Toll receptors) transduce signals for NF-κB activation via the TNF receptor associated factor, TRAF 6. Toll receptors signal via the MyD88 adapter, but a MyD88 independent pathway is also apparent in DCs.50 The implication of these experiments is that a vaccine for strong T cell-mediated immunity will require two major components. First the vaccine and/or the encoded antigens need to be captured and processed by DCs, and second, the vaccine must comprise a maturation stimulus to ensure NF-κB activation and the potent T cell stimulatory function of these cells.

Dendritic Cells as Nature’s Adjuvant

The above tissue culture studies were extended by three major lines of evidence that DCs were major antigen presenting cells for initiating immunity in situ: 1) The distribution of DCs in vivo was consistent with their role as physiologic adjuvants (Figure 1); 2) DCs efficiently captured antigens administered to animals and were the main cell type expressing the antigen in a form that is immunogenic to T cells; and 3) DCs could be used in adoptive transfer experiments to actively immunize mice and rats (Figure 2). Therefore, mature DCs serve as powerful and natural adjuvants. This has been extended to humans (next section).

Figure 1. Distribution of dendritic cells in vivo.

Figure 1

Distribution of dendritic cells in vivo. DCs are derived from proliferating progenitors in the bone marrow. The progenitors are responsive to flt-3L and G-CSF. The nonproliferating progeny or DC precursors are found primarily in blood as monocytes and (more...)

Figure 2. Demonstrating the role of DCs as adjuvants in vivo.

Figure 2

Demonstrating the role of DCs as adjuvants in vivo. If DCs from lymphoid tissues, or DCs dervived from progenitors, are charged ex vivo with antigens, exposed to a maturation stimulus, and then injected into syngeneic animals or autologous humans, the (more...)

Distribution of Dendritic Cells in vivo

The distinctive tissue distribution of DCs (Figure 1) was outlined using a common set of criteria, especially the isolation of MHC II rich, stellate, nonadherent, nonphagocytic cells. The cells were abundant in the T cell area of peripheral lymphoid organs: spleen, lymph node, and Peyer’s patch,51 where they formed an extensive network of MHC II rich processes. Even though DCs were outnumbered by B cells in suspensions of lymphoid cells, 50 to 1 approximately, their abundant MHC II products and distribution dominated the T cell area. DCs were also identified in peripheral tissues, like skin or airways, as well as afferent lymphatics5256 and blood.9,57 Therefore DCs are distributed in a way that facilitates antigen capture and transport to lymphoid organs.

It is known that immune responses begin in peripheral lymphoid tissues, and that immunization leads to substantial but temporary depletion of antigen-reactive cells from the circulation. DCs help to explain this finding. DCs are designed to take antigen from wherever it is deposited, migrate to the lymphoid organs, and then efficiently select relevant T cell clones from the recirculating pool to start the immune response, as has been observed directly in situ.58,59 Following clonal expansion and differentiation in the T cell area, T cells can reenter the circulation, returning as effectors to the site of antigen deposition. DCs in contrast are not found in efferent lymphatics. In sum, when antigens in the periphery are captured by DCs, they can gain access to the rare, antigen-specific, naïve T cells in the recirculating pool. The DCs then induce numerous activated effector T cells, which return to the initial sites of inflammation. Therefore the distribution of immune cells in situ is such that events in the afferent limb of an immune response are orchestrated by DCs, while events in the efferent limb are the proviso of many other antigen presenting cells.

Efficient Capture of Antigens by DCs in vivo

If antigens were administered in vivo by different routes (skin, airway, muscle, gut, blood stream), and then the corresponding depots of DCs were isolated (Figure 2), the DCs presented antigen to specific T cells in culture.55,56 In fact, when a complex organ like spleen was analyzed, DCs were the main cell type capturing antigens in vivo in a form immunogenic for T cells.60 This does not imply that DCs are the only cells to capture antigens, or even to form MHC-peptide complexes, but instead that DCs are the main reservoirs of “immunogen”.

Antigen Pulsed DCs Prime T-Dependent Immunity in Rodents

DCs were used as adjuvants to actively immunize or prime rodents. The DCs were obtained from lymphoid organs and lymph, or generated from progenitors in marrow. The cells were pulsed with antigens during their maturation ex vivo and used to prime mice or rats in an antigen-specific manner (Figure 2). The induced T cell immunity was specific for the antigens and MHC of the injected DCs.26,56 When tested, mature DCs were more effective in priming T cells.25,6163 It was also feasible to elicit protective anti-microbial and anti-tumor immunity using antigen-pulsed DCs without other adjuvants.6466 The DCs in these experiments had undergone maturation ex vivo prior to injection. Therefore these adjuvant findings need not represent DC function in the steady state in vivo, where a role in peripheral tolerance is becoming apparent (next section).

Human DCs Control the Quality of the Immune Response: New Findings from Studies in Humans

It has been difficult to identify adjuvants for amplifying strong T cell-mediated immunity in humans. Once it became possible to prepare large numbers of DCs from different precursors, it was exciting to test their capacity to elicit immunity in humans, as observed in experimental animals above (Figure 2). In fact, strong immunity has now been induced with DCs in humans, both Th1 type CD4 helpers and CD8 cytolytic T lymphocytes.

Initial Use of DCs to Actively Immunize Patients Against Cancer

Cancer has been the first setting in which autologous DCs have been charged with antigens ex vivo, exposed to maturation stimuli, and then reinfused to try to elicit immunity. In all cases, the vaccinations have been nontoxic. Although this approach is in its early stages in terms of methodology, DC vaccination already has expanded T cell immunity, detectable in fresh blood samples from the vaccinees.67,68 To date, when other adjuvants have been assessed in humans, it is typically necessary to measure immunity after prolonged restimulation of the blood sample in culture. Furthermore, some striking regressions in the setting of metastatic disease have been reported following vaccination,6971 again using methods that only begin to exploit DC physiology.

Antigen-Bearing DC Reliably Expand T Cell Immunity in Healthy Volunteers

The apparent safety of DCs as adjuvants led to studies in healthy volunteers, to determine immune efficacy in a vaccine vs. therapeutic setting. DCs were pulsed with model antigens. These were keyhole limpet hemocyanin, KLH, as a priming protein; tetanus toxoid as a recall protein; and influenza matrix peptide as a recall CD8 T cell epitope. The injected DCs rapidly expanded T cell immunity.72 The conditions of these new DC vaccinations experiments have been difficult to predetermine. It was elected to inject 2–4 × 106 mature DCs subcutaneously. However, much needs to be learned about the dose, frequency and route of DC administration. Many features of DC biology (below) also remain to be manipulated.

Improving the Quality and Affinity of the T Cell Response with Mature DCs

Subsequent studies in humans revealed two critical ways in which DCs improved the quality of the T cell response (Table 1). First, mature DCs rapidly polarized the CD4 T cell response to the Th1 type. After a single injection of KLH-pulsed DCs, the antigen-dependent cytokine producing cells in blood made IFNγ but little or no IL-4.73 Th1 IFNγ-secreting cells are known to be more protective and lead to better memory in experimental models of tumor growth and virus infection.7477 Second, mature DCs pulsed with an MHC class I restricted peptide, are able to improve the quality of T cell memory. After a second booster dose of peptide-pulsed DCs, the antigen-specific CD8+ T cells recognized antigen at 10–100 fold lower doses than observed initially.78 Likewise, when booster doses of DCs were given with tetanus toxoid protein in cancer patients, strong delayed type hypersensitivity reactions were induced by the 3rd dose.79 In other words, DCs not only control T cell priming, but they also influence the quality of the T cell response and can boost T cell memory (Table 1).

Table 1. Classical and new functions for DCs.

Table 1

Classical and new functions for DCs.

Silencing and Regulating Immune Responses with Immature DCs, One Mechanism for DC-Based Tolerance

The biggest surprise came when immature DCs were tested as APCs. It had been assumed from several studies in mice25,6163 that immature DCs were simply ignored, because they lacked several accessory properties to be outlined in the next section. However the immature DCs actually silenced the CD8 IFNγ producing cells that were present prior to vaccination.73 The silencing was specific for the antigen that had been given on the immature DCs, and it was accompanied by the appearance of IL-10 producing T cells. In one of the individuals vaccinated with immature DCs, sufficient blood was available to show that functional regulatory T cells were induced (unpublished). More detailed in vitro experiments have shown that immature DCs elicit IL-10 producing regulatory T cells,80 which markedly reduce the function of preformed Th1 type cells. Therefore, DCs can both enhance and dampen immunity in an antigen-specific way, and their state of maturation has a critical role in these distinct outcomes (Table 1).

Induction of regulatory T cells is one of the ways that DCs could mediate peripheral tolerance, an emerging area of DC function. The importance of DCs in tolerance was stimulated by the observations that DCs could process antigens from dying influenza-infected cells.81,82 During influenza infection, there is extensive cell death, e.g., the airway epithelium is almost entirely killed. It is reasoned83 that DCs have no way to distinguish microbial from self antigens in the dying airway epithelium, and likewise, to distinguish microbial proteins from the many environmental nonself proteins in the airway. Yet recovery from influenza or other infections is generally not associated with chronic immunity to the airway cells or its lumenal proteins. It has therefore been proposed that the critical function of DCs in the steady state is to induce tolerance, either through the induction of T regulatory cells, or the deletion and anergy of antigen-responsive T cells. Both of these functions have now been demonstrated for DCs.80Therefore, the immune response is not solely controlled by DC maturation22 or danger84 or microbial pattern recognition.85 Instead, DCs in the steady state must first induce peripheral tolerance to those peptides from environmental proteins and self tissues that could later be presented when infection induces DC maturation. In this way, the immune response can safely focus on microbial antigens.

Other Types of Immune Responses and Subsets of DCs

Dendritic Cells Influence Other Classes of Lymphocytes, not Just T Cells

DCs are able to control other parts of the immune system. These other classes of lymphocytes have been the subject of only a few studies, primarily in culture. DCs have direct effects on human B cells inducing growth and high-level Ig secretion, even switching to the IgA isotype.86 Interestingly, monocyte-derived DCs but not Langerhans cells have this B cell stimulatory function.87 DCs present glycolipids to NK-T cells, resulting in high levels of IL-12 production.88 Through this IL-12, and by direct interactions,89 DCs have the potential to recruit NK cells.90 Therefore, with the appropriate stimuli and ligands, DCs can control several types of lymphocytes, not just T cells (Table 1).

DCs Link Innate and Active Immunity

DCs have an innate capacity to respond rapidly to microbial stimuli, and in so doing, set in motion the adaptive immune response. Microbial extracts can selectively induce high-level production of IL-12 by DCs in the T cell areas of lymphoid organs in mice.91 This IL-12 would be expected to recruit NK cells and help polarize naïve T cells to the Th1 type. T cell area DCs make IFNγ,92 while plasmacytoid DCs release prodigious amounts of interferon-α.93 Interferons activate NK cells and increase antigen presentation on MHC class I and II products, in addition to their more standard anti-viral functions. DCs can directly stimulate NK-T88,94 and NK cells,89 which can kill certain virus-infected and tumor targets. Innate NKT and NK cells themselves make protective cytokines, especially interferon-g, to increase antigen presentation and thereby adaptive immunity. These many and powerful roles of DCs in innate responses are proving to be a major sphere of DC function.

Table 2. Specialized mechanisms for antigen capture and MHC-peptide formation in DCs.

Table 2

Specialized mechanisms for antigen capture and MHC-peptide formation in DCs.

Subsets of DCs

In addition to distinct stages of DC maturation, distinct forms of immature and mature DCs are being identified. In mice, peripheral lymphoid tissues, especially spleen, have at least two subsets: one with high expression of CD8 and the DEC-205 endocytosis receptor (below) and low expression of CD11b integrin; the other has low CD8 and DEC-205 but high CD11b integrin.95 Following isolation, the CD8 subset is main adjuvant for Th1 type immunity,96 while in vivo, the CD8 subset appears to be the main cell that presents exogenous antigens on MHC class I97(see below). In human blood, there are separate subsets of CD11c positive and CD11c negative DC precursors that are also called DC1 and DC2.98 The former can produce very large amounts of IL-12 and the latter very large amounts of IFNα.93 When DCs are generated from CD34 progenitors, at least 2 distinct types of DCs are produced: Langerhans cells, and interstitial or dermal DCs.87 Only the latter can stimulate B cell differentiation directly,99 while Langerhans cells may stimulate CD8 T cells better. This is a very brief summary of DC subsets, an important emerging area of DC biology. Vaccine design has yet to exploit these subsets.

Some Mechanisms Underlying DC Function

Dozens of molecular events underlie DC function and the control of the immune response. It is helpful to divide this intricate physiology into sets of signals, though different authors have different ways of doing this. Here we refer to signal 1 as the many events involved in the formation of ligands for the TCR, i.e., antigen presentation; signal 2 as the many surface molecules that mediate T cell adhesion and activation, as well as secreted cytokines; and signal 3 as the mechanisms mediating DC function in situ.

MHC-Peptide Complex Formation—Signal 1

Immature DCs are able to take up substrates through pinocytosis and phagocytosis. A maturation stimulus subsequently regulates DC endocytic activity, proteolysis, and the formation and transport of MHC-peptide complexes. Upon maturation, uptake of fluid and particles by pinocytosis and phagocytosis decreases, through the inactivation of Cdc42, a Rho-family GTPase.31 DCs also can downregulate the levels of cystatin C within lysosomal compartments.100 The loss of cystatin C, an inhibitor of cathepsin S, should increase proteolysis of the invariant chain, which in turn should increase exchange of antigenic peptides with CLIP and movement of the MHC-peptide complex to the cell surface. Proteolysis of antigens through other cathepsins also can be regulated by cytokines in DCs.101 In sum, during maturation, many DCs typically cease taking up additional substrates but efficiently convert acquired substrates into MHC-peptide complexes.

DCs have an unusual endocytic receptor termed DEC-205.102 This receptor traffics through the endocytic system in a distinct way, being able to enter and recycle through MHC II positive late endosomes or lysosomes. The ligand recognition properties of DEC-205 are not yet known, but targeting of surrogate ligands through this receptor has the potential to increase the efficiency of antigen presentation on MHC II by 10–100 fold.103 At this time, DEC-205 is an excellent candidate for future attempts to target vaccines better to DCs.

A striking feature of DCs is termed the exogenous pathway of presentation on MHC class I, or cross presentation. Immune complexes (Fcγ receptor) and dead or dying cells (the avb5 integrin is one relevant receptor) are efficiently taken up by immature DCs.82,104 Somehow these endocytosed, nonreplicating substrates gain access to the necessary proteosomal and TAP machinery for presentation on MHC class I. DCs also present nonreplicating forms of viruses,105 but here the viral envelope or capsid proteins likely deliver viral antigens to the cytoplasm. Normally, MHC class I molecules are charged with peptides that are newly synthesized in the cytoplasm (the endogenous pathway), but with DCs, inanimate immune complexes and dead cells are processed onto MHC I (the exogenous pathway).81,106 DCs also present peptides from dying cells on MHC class II with very high efficiency.107,108 A fascinating recent example is the EBNA1 molecule that DCs efficiently process from Epstein Barr Virus transformed B cells.108 Epstein Barr Virus causes an acute lytic infection of B cells, e.g., during infectious mononucleosis. The processing of dying B cells by DCs may explain why healthy carriers of EBV typically show a Th1 polarized, CD4 T cell response to EBNA1109 and are able to contain this transforming virus.

The processing of dead cells at first seems to violate the beauty of MHC restricted recognition, whereby T cells focus their function on targets of replicating microbial antigens. Cross presentation of dead cells would allow T cells to attack uninfected targets that present peptides via the noninfectious, exogenous pathway. However cross presentation appears primarily to be a function of DCs, and it is proposed that its major role is to allow DCs to induce tolerance. The reasoning is as follows. Following microbe-induced cell death, phagocytic immature DCs would seem unable to distinguish microbial proteins from cellular self proteins, or proteins that are normally resident in the external environment like the airway and intestine. In other words, if “maturation”, “danger”, or “pattern recognition” were the only control of immunogenicity as discussed above, then during infection we would all become immunized to the many environmental and self antigens that DCs would inevitably process (during the maturation associated with microbial infection). Therefore it is argued that DCs in the steady state (e.g., while you are reading this chapter) are specialized to cross present antigens, captured as a result of normal cell turnover.83 Without a maturation stimulus in the steady state, these self proteins are presented in a tolerogenic way, perhaps through the induction of regulatory T cells,73,80 or through deletional and anergic tolerance.110 Then, when the DCs are subsequently required to process cells dying during infection and associated maturation stimuli, the immune response focuses in an MHC-restricted way on the infected cells, and importantly, on the microbe rather than self and environmental proteins. As a corollary, those self and environmental peptides that are not presented by DCs in the steady state are in essence non-self. Neurons for example do not undergo extensive turnover or capture by DCs, so the exogenous pathway may not be available to elicit tolerance to many self peptides in neurons.

The capacity of DCs to present cellular antigens in a tolerogenic way is of importance in DNA vaccination. This type of vaccine stably expresses antigens in muscle or skin, and over the long term, there may not be any inflammatory stimulus at the injection site. Therefore there is a chance that the vaccine can elicit tolerance rather than immunity. As we shall discuss below, the priming of CD4 T helper cells during vaccination, may be critical to ensure that the stable reservoir of vaccine antigen sustains memory rather than induces tolerance.

T Cell Binding and Costimulation—Signal 2

The potency of DCs is far from explained, but several mechanisms are beginning to emerge. Again, these mechanisms can be influenced by maturation. A lot of the work has been done with what are termed myeloid, particularly DCs produced by stimulation with GM-CSF from mouse bone marrow progenitors and human monocytes.

DC-SIGN is a newly described C-type lectin that binds to ICAM-3 on resting T cells. It is proposed that DC-SIGN (DC Specific, ICAM-3 Grabbing, Non integrin) allows DCs to form loose conjugates with T cells in an antigen-independent fashion.111 Once the loose DC-T cell conjugates form, it is further proposed that the immunologic synapse can begin to assemble and fire. More direct work is needed to examine DC-SIGN function and synapse formation in naïve T cells.

Many costimulators are expressed by mature DCs including CD54/ICAM-1, CD48 and CD58/LFA-3, several B7 family members including CD80 and CD86, and some TNF related costimulators like 4-1BB ligand and BAFF/BlyS. The powerful CD86 co-stimulator is of some interest. It is very abundant on DCs relative to other leukocytes, and it is rapidly upregulated during maturation.112,113 At the DC surface, CD86 is clustered together with MHC-peptide in surface patches.114 The formation of these surface aggregates suggest that DCs are fully prepared, before they contact the T cell, to co-assemble TCR and CD28 molecules and form the supramolecular immunologic synapse. If it is important for CD28 to be juxtaposed to the TCR complex for costimulation to take place, then mature DCs are designed to set up a functioning APC-T cell synapse with naïve T cells.114 Much of the published work on immunologic synapse formation has used previously activated T cells, but the abundance and distribution of B7 molecules on DCs may be critical to set up the synapse in naïve T cells.

The B7 family is proving to have additional unusual features on DCs, particularly as it relates to Th1/Th2 polarization and the quality of the immune response. Mature DCs can lack ICOS-ligand, a key Th2 polarizing B7 family member.115 Other DCs express the new B7-DC and B7-H3 molecules that can induce IFNγ from naïve T cells.116 These new B7 molecules could account for the strong Th1 polarizing activity observed when DCs are used as adjuvants in humans.73

Upon receipt of a maturation stimulus, DCs can make several cytokines that act on other cells. IL-12 can be made in particularly large amounts. The new IL-12 relative, IL-23, is also produced,117 as is the memory sustaining cytokine IL-15.118 The control of IL-12 production is intricate.119121 Other cytokines (GM-CSF, IL-4, IFNγ) influence bioactive IL-12 synthesis following encounter of a maturation stimulus. Abundant cytokine production ceases within 12 hours of receiving a maturation stimulus,121,122 whereupon the DCs have been termed “exhausted”.122 Nevertheless, these DCs are far from exhausted in terms of their capacity to stimulate T cell immunity, including Th1 responses in vivo.73 IL-1β also can be made by DCs and may act back on the DCs to stimulate some of the changes in maturation. In the past, IL-1 was thought to be a major lymphocyte activating factor, but its activating role seems directed more to DCs and their development.123,124 Plasmacytoid DCs make very large amounts of IFNα but little IL-12, while monocyte-derived DCs seem to make relatively little IFNα but very large amounts of IL-12.93 Immature DCs can make abundant IL-10,125,126 which would be expected to be immunosuppressive. Importantly, mature DCs resist the immunosuppressive effects of IL-10.127 Therefore DCs can produce many costimulatory cytokines and membrane molecules, and all seem to be critically influenced by the process of maturation.

Mobilization and Movement in vivo—Signal 3

Figure 1 diagrams some of the sites where DC function can be manipulated in vivo. DCs traffic through many tissues in the steady state. For example in rat lung epithelium and mouse spleen, DCs are turning over with a half time of just 2 days.128,129 There is a constant traffic of DCs in the lymph, since cannulation always reveals a substantial flux of several thousand DCs per hour.52,54,55 One source of DCs in lymph could be blood monocytes. Important cues for monocyte differentiation into DCs can be provided during their reverse transmigration across endothelium.130 MIP-3α acting on CCR6 is a candidate to explain the steady state recruitment of Langerhans cells to the epidermis,131 and other immature DCs to mucosal associated lymphoid tissues.132 DCs can also be mobilized in larger numbers. For example, precursor and immature forms of DCs increase 5–10 fold in blood and other tissues following systemic administration of flt-3 ligand and G-CSF.133,134

During two powerful immune stimuli, contact allergy and transplantation, epidermal LCs in situ begin to migrate and to mature, i.e., MHC II and costimulatory molecules are upregulated.135 A hallmark of DC maturation is the upregulation of functional CCR7 receptors for CCL19 and CCL21, two chemokines that are made constitutively in the T cell area (the sources might be DCs, other stromal cells, and certain endothelia).136139 CCR7 knockout mice show poor migration of epidermal Langerhans cells in response to contact allergens.140 Recently, it has been found that multidrug transporters (MDR-1 and MRP) can participate in DC migration, probably by pumping cysteinyl leukotrienes, which in turn improve CCR7 responsiveness.141 CD40L, which is found on mast cells and platelets and not just activated T cells, also is critical for DC mobilization in situ.142

DCs produce several chemokines. The most abundant are: CCL19 (ELC or MIP-3β), which recruits naïve T cells via CCR7;139 DC-CK1 or PARC, which also recruits naïve T cells,143 but the chemokine receptor is not yet known; CCL18 (TARC), which recruits central memory and Th2 cells via CCR4;144,145 CCL22 (MDC, ABCD-1), which also reacts with CCR4 on memory and Th2 cells;146 and CX3CL1 (fractalkine), which recruits activated T cells cells via CXCR3. Interestingly, mature DCs release fractalkine,147,148 and this could attract immature DCs such as the CXCR3 expressing plasmacytoid DCs.149 Immature DCs also make several inflammatory chemokines, like CCL3 (MIP-1α), CCL4 (MIP-1β), and CCL5 (RANTES),145,150 which would recruit more DCs via CCR5. The production of chemokines by DCs is so intricate that many reviews have been needed.136,151

A current conundrum is to identify the controls on DC migration in the steady state vs. inflammation. As mentioned above, immature DCs are migrating constitutively in lymphatics. What directs this migration? Might fractalkine produced by DCs in the T cell areas147 control the movement of immature DCs from the periphery? What are the roles for the marked upregulation of CCR7 on maturing DCs? Does the CCR7 system have a costimulatory role for the immune response beyond a role in chemotaxis of mature DCs? Does CCR7 allow DC migration to be more rapid during inflammatory stimuli? The control of DC migration and function in the T cell area is central to understanding the consequences of DC traffic in the steady state and during mobilization with a vaccine, since immature DCs may lead to tolerance and/or T regulatory cells and mature DCs to strong Th1 and CTL immunity.

After DCs reach the lymph node, their life span is short because the cells are not found in efferent lymph. Nonetheless, lifespan can be prolonged by ligation of CD40 or TRANCE-R, thus enhancing immunogenicity.39 Given all the mechanisms that are being identified to enhance DC numbers and function in vivo during infection and inflammation, it may be valuable to mimic these pathways to enhance the efficacy of vaccines, and also, to decrease the proposed tolerogenic roles of DCs in the steady state.

DCs as Mediators of DNA Vaccination

The implication of the above findings is that the efficacy of a DNA vaccine would be increased if the encoded antigens were presented by mature DCs. The evidence that DCs play a key role in DNA vaccination comes from several avenues of experimentation in mice. The experiments also suggest sites for further research to improve DNA vaccine efficacy.

Bone Marrow Derived Cells, not Somatic Cells, Present Antigens Encoded by DNA Vaccines

Several publications have monitored the MHC restriction of T cells that are primed by DNA vaccines in bone marrow chimeric mice. In these animals, parental marrow (MHC-A) is used to reconstitute F1 (MHC-A × B) recipients. Therefore the MHC expressed by somatic cells e.g., the muscle or skin cells that are the main sites for expression of the injected DNA, differs from the MHC of the bone marrow derived cells, e.g., the DCs. Nevertheless, the vaccinated T cells typically recognize antigen in the context of the bone marrow (MHC-A) and not the somatic cells (MHC-B as well as MHC-A).152154 This indicates that leukocytes, not somatic cells, prime T cells during DNA vaccination of mice, even though the vaccine is expressed primarily in nonhematopoietic cells.

DCs Are Directly Transduced During DNA Vaccination in Mice

In the above chimera experiments, the bone marrow derived cells could either be directly transduced by the DNA vaccine, or pick up proteins expressed in non bone marrow derived cells. Casares et al detected DNA in DCs from DNA vaccinated mice, but not in other cells.155 When DCs were isolated from the vaccinated mice, these cells were the main presenters of the vaccine antigen, an influenza hemagglutinin, to MHC class II restricted CD4 T cells.155 Nonetheless the isolated DCs presented antigen poorly relative to that seen when antigenic peptide was added directly to the tissue culture assay for presentation to CD4 T cells. This means that the amount of antigen presented by individual DCs from vaccinated mice was very small, or more likely, the frequency of DCs presenting antigen was small. Bot et al extended the data with an MHC I restricted epitope, the influenza nucleoprotein.156 They visualized cells expressing native viral nucleoprotein encoded by the DNA vaccine. The protein was expressed and targeted to the nucleus in ˜ 2% of the DCs from the DNA vaccination site. These DCs were sufficient to induce virus specific CTLs following injection into the spleens of naïve mice.156 Akbari et al157 scarified the ears of mice with a full length DNA for complement C5. They showed that DCs were the main cell expressing C5 antigen in the draining lymph node, while keratinocytes expressed the DNA in the skin. Again ˜2% of the DCs were estimated to express the vaccine DNA, which could not be detected beyond 2 weeks in the node. These experiments all reveal that DCs in the draining lymph nodes have been transduced by DNA vaccines in situ, but they do not formally distinguish whether in addition, the lymph node DCs capture vaccine antigen from other cells.

Porgador et al designed an experiment to prove that directly transduced DCs were the major source of presented antigen at the early time points after vaccination.158 They co-administered two DNA plasmids, one encoding the vaccine antigen and the other human CD4 as a marker. They again found that DCs were the main cell presenting the vaccine, but in addition, the presenting cells could be selected with an antihuman CD4 antibody. The latter would fail to react with most of the nontransduced DCs picking up antigens by the exogenous pathway.

Taken together, these results show that DCs are transduced during DNA vaccination and that these transduced DCs are the main source of presented antigen in the lymphoid tissues shortly after vaccination. Clearly the frequency of DNA transfected DCs has been very small in all four studies above, either at the DNA injection site or in the draining lymphoid tissues where the immune response is likely to be generated. Furthermore, DCs might also acquire vaccine antigen from other cells, especially later in the course of vaccination when the antigen is primarily expressed in nonhematopoietic cells at the vaccination site.

After the Priming Phase of DNA Vaccination, Are DCs Continuing to Cross Present Antigen from Other DNA Vaccinated Cells and Is This Important for Expanding Vaccine Immunity?

These questions have not yet been answered directly but may be critical unknowns in the efficacy of vaccination, whether it involves plasmid DNA vaccines or other vector-based vaccines. In the work of Akbari et al,157 DNA bearing DCs could not be detected for >2 weeks after vaccination whereas CD4 memory T cells persisted >40 weeks. Do small numbers of transfected DCs prime the immune system early on, but then additional DCs continue to capture antigens released or phagocytosed from transduced somatic cells (muscle, fibroblasts, keratinocytes) in vivo? Akbari et al showed that DCs could acquire antigen from keratinocytes in culture, as long as the skin cells were killed by irradiation, presumably enhancing phagocytosis and cross presentation by the DCs as discussed above. There are other studies showing that bone marrow derived cells, possibly DCs, can acquire antigens from somatic cells,159 e.g., a muscle transplant, expressing the DNA vaccine.154

A critical part of immune memory is the interaction of CD4 helpers and CD8 cytolytic T cells. When a CD4 T cell acts on a DC, e.g., via CD40L, the DC matures and presents antigen better to CD8 T cells.160162 Antigen-specific CD4 T cells are most likely primed by DCs acutely during DNA vaccination, but they may also continue to act chronically on DCs that capture antigens from vaccine-transduced somatic cells, especially transduced cells that die during normal cell turnover? This would allow the DNA-transduced muscle or skin to act as a source of antigen that sustains or expands the immune response. In mice, CD4 helper T cells can sustain CD8 killer T cell function following DNA vaccination,163 although the time at which the T cells are acting (priming, memory) is not yet clear. CD4 Th1 helpers appear critical for CD8 T cell memory in other situations, especially tumors74 and chronic viral infections.76,77 During the priming phase of the immune response, when there is more likely to be inflammation and other stimuli (e.g., the DNA vaccine itself, next section) to mature the DCs, CD4 T cells may not be essential. This is because mature DCs are capable of stimulating CD8 T cells in the absence of helper cells.16,17 In the longer term, however, there is unlikely to be a stimulus for DC maturation, except if DCs present peptides on MHC II and mature in response to CD40L38,62 or other ligands164,165 on CD4 helper cells. Therefore it will be helpful in DNA vaccination to monitor more closely the presence and kinetics of different types of CD4 and CD8 T cells. It will probably be important to try to increase both arms of the T cell response to enhance immunogenicity in the priming and memory phases of vaccination.

Responsiveness of DCs to the Adjuvant Action of DNA Vaccines and CpG Oligodeoxynucleotides (ODNs)

Although only 1–2% of DCs express vaccine DNA in lymph nodes, these vaccines (including the DNA vector itself) globally activate most DCs in the node.157 In other words, most DCs—not just the transfected cells—upregulate their costimulatory molecules like CD40, 54, 80 and 86 following administration of DNA. As mentioned, DCs are responsive to CpG deoxyoligonucleotides (ODN’s), undergoing maturation in vitro4749 and in vivo.50 Therefore a DNA vaccine has the capacity to carry out the two key features of vaccination: to express vaccine antigens in DCs and to mature even nontransfected DCs to their potent stimulatory function. While direct transduction of DCs is valuable, one could argue that as long as DCs are being matured while acquiring antigens from other sources (like DNA transfected muscle or skin), the net effect should be the same, strong immunity. It may not be straightforward to increase the number of DCs that are directly transduced by the DNA vaccine, but it may be more feasible to enhance cross presentation and maturation by many nontransduced DCs.


There may be many points at which DCs play a role in DNA vaccination. DCs can be directly transfected and prime Th1 CD4 helpers and CD8 killer cells that together provide strong T cell-mediated immunity. It is possible that DCs also acquire antigens from other transfected cells, to further boost the response and to provide the kind of long-term memory upon which successful vaccination depends. DNA vaccination itself can act as a distinct maturation stimulus for DCs, a vital step towards immunogenicity, whether the DC acquires antigen directly by transduction or by cross presentation. These issues will require further research, but they probably lie at the heart of improving the efficacy of DNA vaccination and eventually, the use of DNA vaccines to regulate and tolerize the immune system as well.


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