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Dendritic Cells in Immune Response Induction

Department of Tumor Immunology, University Hospital Nijmegen, The Netherlands

Key Words. Dendritic cell • Antigen-presenting cell • Primary immune response • T lymphocyte • Antitumor • MHC class I • MHC class II

Correspondence: Dr. Gill Marland, Department of Tumor Immunology, University Hospital Nijmegen, Philips van Leydenlaan 25, 6525 EX Nijmegen, The Netherlands.

	Abstract

Top Abstract Introduction Ontogeny of DCs Isolation and In Vitro... DC Phenotype Primary Immune Response... MHC Class I-Dependent Responses MHC Class II-Dependent Responses DCs as Inducers of... Concluding Remarks Acknowledgements References

 
The study of dendritic cells (DCs) has seen a rapid expansion in recent years, and their importance within the immune system is now widely recognized. Along with B lymphocytes and mononuclear phagocytes, DCs make up what are known as the professional antigen-presenting cells (APCs). These are cells which are capable of highly efficiently presenting antigens to the immune system in the context of both major histocompatibility complex class I and class II molecules. What makes DCs stand out from other professional APCs, however, is their seemingly unique ability to present antigen to T lymphocytes which have had no previous contact with antigen. This gives DCs a central role in the initiation of immune responses, and creates possibilities for their exploitation in the development of therapeutic strategies against tumors and other diseases.

What are the characteristics of DCs which enable them to carry out their specialized function? This is a question which is currently gaining much interest. While higher expression levels of the antigen-presentation machinery may account for this, there may also be as yet unidentified mechanisms at work. In this review, we will discuss the evidence for DC-mediated priming of both CD4⁺ and CD8⁺ naive T cells, both in vitro and in vivo, current ideas on how DCs achieve their potent function and the implications for the design and execution of immunotherapeutic strategies.

	Introduction

Top Abstract Introduction Ontogeny of DCs Isolation and In Vitro... DC Phenotype Primary Immune Response... MHC Class I-Dependent Responses MHC Class II-Dependent Responses DCs as Inducers of... Concluding Remarks Acknowledgements References

 
Dendritic cells (DCs) are a diverse system of cells which have been identified in all tissues of the body, with the exception of the brain. First described less than 25 years ago [1], their study has been hampered by two main factors. First, they are present in the blood and tissues in very low amounts. Among peripheral blood mononuclear cells (PBMCs) they account for less than 1%. Second, there are as yet no known DC-specific cell surface antigens with which to aid their positive identification. Despite these difficulties, significant progress is being made towards an understanding of DCs, particularly with respect to their role in antitumor immunity, allograft rejection and the pathogenesis of AIDS. The lineage relationship of DCs to other leukocytes is not completely understood, and even within the DC system there is considerable heterogeneity. They remain, therefore, most readily defined in terms of their function, notably their strong accessory function for the stimulation of T cells.

	Ontogeny of DCs

Top Abstract Introduction Ontogeny of DCs Isolation and In Vitro... DC Phenotype Primary Immune Response... MHC Class I-Dependent Responses MHC Class II-Dependent Responses DCs as Inducers of... Concluding Remarks Acknowledgements References

 
DCs originate from hematopoietic stem cells, although their stages of differentiation from progenitors are poorly understood. A myeloid origin has been proposed for these cells, based on their shared responsiveness to GM-CSF with monocytes and granulocytes. A common progenitor has been identified in cultures of major histocompatibility complex (MHC) class II negative mouse bone marrow cells which, in the presence of GM-CSF, proliferate and differentiate into mixed colonies containing DCs, monocytes and granulocytes [2]. Furthermore, a progenitor has been identified in human bone marrow which can give rise to both DCs and monocytes, indicating that DCs may branch from the mononuclear phagocyte lineage [3].

Following their departure from the bone marrow, DCs enter the blood and migrate to the tissues. The best characterized tissue DC is the Langerhans cell (LC) of the skin. LCs express Fc receptors (FcRs) which enable these cells to take up antigen specifically. On culturing both human and mouse LCs, however, FcR expression is lost while the expression of MHC class I and II is increased [4, 5]. As demonstrated in the murine system [4], this correlates with a 10-fold increase in activity in the mixed leukocyte reaction (MLR), which is indicative of their T cell stimulatory capacity. Based on these findings, a model delineating two main stages of DC maturation has been proposed. First, immature DCs are capable of taking up and processing antigen, and second, mature DCs are efficient at presenting antigen to T cells. In vivo tissue-resident DCs, such as LCs, could be classed as immature DCs. Following antigen uptake, these cells are mobilized and migrate via the afferent lymph and blood to secondary lymphoid organs where they stimulate T cell responses. The mobilization of these DCs is concomitant with their differentiation into mature DCs.

	Isolation and In Vitro Generation of DCs

Top Abstract Introduction Ontogeny of DCs Isolation and In Vitro... DC Phenotype Primary Immune Response... MHC Class I-Dependent Responses MHC Class II-Dependent Responses DCs as Inducers of... Concluding Remarks Acknowledgements References

 
Conventional methods for the isolation of DCs from PBMCs involve the successive depletion of populations of non-DCs [6]. T cells are removed by rosetting with neuraminidase-treated sheep red blood cells, and monocytes by their adhesive properties or by panning with antibodies that bind to FcRs. B cells and natural killer cells are removed following centrifugation over metrizamide gradients, yielding a low-density fraction which is highly enriched for DCs. As an additional step, DCs can be further purified by selecting for cells which do not express known lineage markers such as CD3, CD19, CD56 and CD14. While a reasonably pure population of DCs can be obtained, these methods are time-consuming and often result in low yields of cells with an unknown activation status.

In order to circumvent the difficulties encountered during the isolation of peripheral blood DCs, methods have been developed for the generation of DCs in vitro. Starting with either bone marrow or blood cells, murine DCs were generated following culture in the presence of GM-CSF [7, 8]. GM-CSF could similarly be used in the generation of human DCs, but required in addition tumor necrosis factor (TNF-) when starting with CD34⁺ progenitor cells [9], and interleukin 4 (IL-4) when starting with peripheral blood [10, 11]. From peripheral blood it has been found that GM-CSF in combination with IL-4 results in a yield of DCs which is 40- to 80-fold higher than would normally be expected from peripheral blood [10, 11]. While a small proportion of these cells may arise from proliferating progenitors present in the blood, it is likely that the majority are derived from monocytes. The relationship between DCs freshly isolated from peripheral blood to those generated in vitro, either from hematopoietic progenitors or peripheral blood, remains to be established.

	DC Phenotype

Top Abstract Introduction Ontogeny of DCs Isolation and In Vitro... DC Phenotype Primary Immune Response... MHC Class I-Dependent Responses MHC Class II-Dependent Responses DCs as Inducers of... Concluding Remarks Acknowledgements References

 
DCs share many features with mononuclear phagocytes, although there are also clear differences which allow for the identification of DCs by phenotypic and morphological criteria (Table 1). DCs are large cells with oval or irregularly shaped nuclei and a cytoplasm possessing few organelles. A characteristic of DCs is their constant formation and retraction of cytoplasmic processes or veils. The heterogeneity of DCs is reflected in the antigenic profiles of the cells isolated from different sources and using different isolation procedures. However, consistent with their role as antigen-presenting cells (APCs), DCs express high levels of MHC class I and class II molecules, as well as the costimulatory molecules CD80 (B7-1) and CD86 (B7-2), and adhesion molecules such as LFA-1, LFA-3 and ICAM-1. They are negative for lineage markers such as CD3, CD14, CD19, CD20 and CD56.

As mentioned previously, the addition of TNF- to CD34⁺ cells is thought to provide an early signal in the induction of DCs. This cytokine has a strikingly different effect, however, on DCs generated by GM-CSF and IL-4 stimulation of PBMCs. When these DCs are further stimulated for 24 h with TNF-, they exhibit an increased T cell stimulatory capacity in an MLR and a 10-fold decrease in presentation of soluble tetanus toxoid to specific T cell clones [10]. These findings suggest that incubation of PBMCs with GM-CSF and IL-4 gives rise to immature DCs which are capable of antigen uptake and processing, while further incubation with TNF- induces their maturation into cells capable of antigen presentation.

As shown in Figure 1, the maturational changes in DCs are associated with changes in expression levels of the surface antigens involved in DC function. Immature DCs, therefore, express higher levels of the molecules involved in antigen uptake, such as FcRs and the mannose receptor. Maturation is accompanied by a decrease or loss of such molecules, and an increase in the expression levels of MHC class I and II and costimulatory molecules.

View larger version (13K): [in this window] [in a new window]   Figure 1. The two main functional stages of DC maturation. The cell surface molecules which play an important role in the two stages are indicated.

	Primary Immune Response Induction

Top Abstract Introduction Ontogeny of DCs Isolation and In Vitro... DC Phenotype Primary Immune Response... MHC Class I-Dependent Responses MHC Class II-Dependent Responses DCs as Inducers of... Concluding Remarks Acknowledgements References

The efficiency with which DCs prime naive T cells has been attributed to high expression levels of MHC class I, class II and costimulatory molecules, retention of antigen for relatively long periods of time [14], and decreased sialylation of MHC molecules [15]. A feature of DCs that may explain their stimulatory capacity is their ability to form large clusters with lymphocytes, a phenomenon that does not occur using other types of APC [16]. Certainly, their irregular shape and ability to form long cytoplasmic processes make each DC well-disposed to make contact with multiple T cells. While a combination of these characteristics may be responsible for their enhanced APC capacity, there may well be further, as yet unidentified, mechanisms at work.

	MHC Class I-Dependent Responses

Top Abstract Introduction Ontogeny of DCs Isolation and In Vitro... DC Phenotype Primary Immune Response... MHC Class I-Dependent Responses MHC Class II-Dependent Responses DCs as Inducers of... Concluding Remarks Acknowledgements References

 
As well as being strong stimulators in an MLR, DCs have been shown to be potent inducers of antigen-specific primary immune responses. When pulsed with MHC class I-restricted viral peptides, DCs were able to induce strong cytotoxic T lymphocyte (CTL) responses against infected or peptide-pulsed targets [17-20]. In DC-mediated induction of these antiviral responses, proliferation of antigen-specific CD4⁺ T cells significantly augmented the development of CTL responses [17, 18, 21]. However the CD4⁺ T cells could be replaced by cytokines derived from these cells, indicating that the presence of the cells themselves was not an absolute requirement [22].

In vitro induction of virus-specific primary CTL responses was shown using DCs as APCs that were either infected with virus or exogenously loaded with MHC class I-binding synthetic peptides. DCs pulsed with total viral antigen were a poor stimulus for the development of CTLs [17], while pulsing with a noninfectious virus led only to a CD4⁺ T cell response [18]. This suggests that DCs have no efficient mechanism for the uptake and delivery of exogenous antigen into the MHC class I processing pathway. However, it is also possible that this phenomenon does occur in DCs but is tightly regulated and restricted to a certain stage of maturation. Alternative strategies for the incorporation of exogenous antigen into the class I pathway of DCs have included direct antigen delivery into the cytoplasm via osmotic lysis of pinocytotic vesicles or via uptake of pH-sensitive liposomes. Using these methods, primary CTLs have been induced both in vivo, in a murine model system using ovalbumin as antigen, and in vitro, using keyhole limpet hemocyanin as antigen [22, 23]. Alternatively, de novo synthesis of the desired antigens by DCs could be accomplished via transfection or viral transduction of antigen-encoding DNA, thus leading to MHC class I presentation [24].

	MHC Class II-Dependent Responses

Top Abstract Introduction Ontogeny of DCs Isolation and In Vitro... DC Phenotype Primary Immune Response... MHC Class I-Dependent Responses MHC Class II-Dependent Responses DCs as Inducers of... Concluding Remarks Acknowledgements References

 
Studies in the mouse have shown that spleen DCs pulsed with antigen in vitro and administered to naive mice were capable of priming T cells [25]. When used in the same system, however, B cells and macrophages were largely ineffective. Restimulation of the T cells in vitro was found to be class II-dependent and the resulting antigen-reactive T cells were predominantly CD4⁺. In a separate study, characterization of CD4⁺ T cells primed by peptide-loaded spleen DCs in vitro showed that, in the presence of IL-4-blocking antibodies, DCs could drive the response toward cells of the Th1 phenotype [26]. Th1 cells, characterized by their secretion of interferon (IFN-), are involved in the generation of CD8⁺ T cell responses, while Th2 cells, which produce IL-4, provide help in humoral immune responses. The ability of DCs to augment a Th1 response was attributed to the production by the DCs of IL-12, a known director of Th1 responses [27].

In vitro studies have shown that human peripheral blood DCs are capable of stimulating previously unsensitized CD4⁺ T cells against a panel of antigens [28]. Antigen-specific T cell activation was dependent upon the presence in the starting population of CD45RA⁺ cells, indicative of naive T cells, and they retained their antigen specificity after long periods in culture. While DCs were an absolute requirement for the initial sensitization, restimulation of these T cell lines could be achieved using macrophages as APCs instead of DCs. This observation gives credence to the idea that the specialized function of DCs is to sensitize naive T cells which are then able to interact with other APCs.

While the supremacy of DCs over other APCs in the priming of CD4⁺ T cells is undisputed, the mechanisms by which they take up antigen are less clear. When compared to macrophages, DCs are weakly endocytic and do not express the same array of FcRs. However, it has been suggested that DCs use macropinocytosis rather than endocytosis to concentrate antigen intracellularly [29]. Unlike other cell types, DCs appear to be constitutively active for macropinocytosis, thus allowing for the continuous uptake of large volumes of fluid. It is also possible that DCs express some as yet uncharacterized antigen-specific receptors. One candidate which has been proposed is the mannose receptor, which is expressed on in vitro-generated DCs. This molecule has previously been associated with the scavenging capacity of macrophages, but could provide some selectivity for foreign antigens due to its ability to bind glycoproteins expressed predominantly on pathogens [29]. Similarly, the murine molecule DEC-205, which is homologous to the mannose receptor, has been associated with antigen uptake [13]. It was observed that rabbit antibodies against DEC-205 were presented 100 times more efficiently to rabbit Ig-specific T cell hybridomas than were rabbit antibodies against irrelevant antigens.

	DCs as Inducers of Antitumor Immune Responses

Top Abstract Introduction Ontogeny of DCs Isolation and In Vitro... DC Phenotype Primary Immune Response... MHC Class I-Dependent Responses MHC Class II-Dependent Responses DCs as Inducers of... Concluding Remarks Acknowledgements References

 
Immunosurveillance of tumor cells by the cellular immune system is often inefficient in vivo, which is reflected in the outgrowth of tumors that are apparently unable to evoke an immune response. An explanation often presented is that the tumor cells are unable to prime antitumor T cells, which could be due to a number of reasons. First, it may reflect an inability of the tumor cells to provide the necessary costimulatory signals for T cell activation. Second, the tumor cells may not express sufficient antigenic determinants that can be seen by the immune system. Third, it could be that the tumor cells secrete inhibitory factors such as transforming growth factor ß (TGF-ß) or IL-10 which have a suppressive effect on local APCs. Since DCs have been shown to be potent inducers of antiviral CTL responses, they may also be instrumental in the induction of T cell-mediated antitumor responses. A suggestion supporting this comes from the clinical observation that infiltration of presumptive DCs into tumor tissue seems to correlate with a favorable clinical prognosis [30].

Several groups have reported the induction of MHC class II-mediated immune responses after stimulation with tumor antigen-pulsed DCs in vitro and in vivo [25, 31-33]. In addition, DCs pulsed with tumor antigen in vitro have been shown to induce tumor resistance in vivo [34-36]. Recently, it was demonstrated that intravenous injection of DCs pulsed in vitro with a single MHC class I-restricted CTL epitope induced a protective CTL response in vivo, capable of resisting a subsequent challenge with tumor cells expressing the relevant epitope [37]. Moreover, eradication of established tumors was achieved using peptide-loaded DCs in the same and two other murine tumor models [38]. Interestingly, in this report therapeutic effects were observed when DCs were pulsed with tumor-derived crude peptide extracts rather than with synthetic peptide. This could broaden the applicability of peptide-pulsed DCs as the need for defining immunogenic peptides is abrogated. In addition, there may be an enhancing effect on CTL generation due to the inclusion of additional class II-restricted epitopes for the stimulation of CD4⁺ T cells.

Based on the data obtained from murine models, it is tempting to speculate that administration of DCs may also be effective in generating cellular immunity to tumors in patients. In testing the validity of such a hypothesis, most studies have been performed on melanoma, as the immunogenic properties of antigens associated with this tumor have been well-defined. Recently, it was reported that upon injection of dendritic-like cells loaded with a melanoma CTL epitope into melanoma patients, tumor-specific CTL could be isolated from the vaccination site and adjacent tumor tissue [39]. This indicates that, indeed, peptide-specific CTLs have been induced by DCs in vivo. Furthermore, vaccination of patients with B cell lymphoma using autologous antigen-pulsed DCs resulted in measurable antibody responses in four out of four patients treated [40]. In addition, clinical responses, including one complete response, were observed in this study.

Until recently, the use of DCs as immunotherapeutic agents has been hampered by their low frequency and difficulties in their isolation, as discussed earlier in this review. However, with the development of methods for the generation of DCs in vitro, sizeable numbers of DCs are now available and have already become valuable tools in the elucidation of antitumor responses. We have shown that using such DCs, CTL responses against melanoma-associated antigen-derived epitopes can be elicited in vitro, from healthy donor-derived peripheral blood lymphocytes [41]. The next step would be to generate large amounts of DCs in vitro, expose them to antigen and reinfuse them into patients. Although this promising immunotherapeutic concept may at the moment be only applicable using broadly expressed antigens in melanoma, a similar approach may be applicable to other solid tumors.

	Concluding Remarks

Top Abstract Introduction Ontogeny of DCs Isolation and In Vitro... DC Phenotype Primary Immune Response... MHC Class I-Dependent Responses MHC Class II-Dependent Responses DCs as Inducers of... Concluding Remarks Acknowledgements References

 
The applicability of DCs in the generation of both MHC class I- and class II-restricted primary T cell responses against a variety of antigens has been demonstrated. However, there are many questions which remain to be answered regarding the function of DCs. In particular, it is still unclear as to what the specific characteristics are which make DCs so different from other professional APCs. While the search for these answers continues, the exploitation of DCs in the clinical setting is already progressing. Especially promising is their usefulness in the generation of tumor vaccines, a field which will no doubt show rapid developments in the near future.

	Acknowledgements

Top Abstract Introduction Ontogeny of DCs Isolation and In Vitro... DC Phenotype Primary Immune Response... MHC Class I-Dependent Responses MHC Class II-Dependent Responses DCs as Inducers of... Concluding Remarks Acknowledgements References

 
Supported by grants ERBCHBICT 930835 from the European Community, and KUN 91245 and KUN 91246 from the Dutch Cancer Society.

	References

Top Abstract Introduction Ontogeny of DCs Isolation and In Vitro... DC Phenotype Primary Immune Response... MHC Class I-Dependent Responses MHC Class II-Dependent Responses DCs as Inducers of... Concluding Remarks Acknowledgements References

 

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints/Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Marland, G. Articles by Figdor, C. G. Search for Related Content PubMed PubMed Citation Articles by Marland, G. Articles by Figdor, C. G.