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Stem Cells, Vol. 14, No. 2, 196-206, March 1996
© 1996 AlphaMed Press

CONCISE REVIEW

Dendritic Cells: Origin and Differentiation

Ranjeny Thomasa, Peter E. Lipskyb

a University of Queensland, Department of Medicine, Princess Alexandra Hospital, Brisbane, Queensland, Australia;
b Division of Rheumatology, University of Texas Southwestern Medical Center, Dallas, Texas, USA

Key Words. Dendritic cells • Differentiation • Rheumatoid arthritis • Stem cell • Precursor • Antigen • Endocytosis • Lineage

Dr. R. Thomas, University of Queensland, Department of Medicine, Princess Alexandra Hospital, Brisbane, QLD 4102, Australia.


   Abstract
Top
 Abstract
Introduction
 Origin
 Differentiation
 Differentiation Stages of DC
 Antigen Processing and DC...
 Conclusion
 References
 
Dendritic cells (DC) are bone marrow-derived cells that are specialized to take up, process and present antigen, and have the capacity to stimulate resting T cells in the primary immune response. DC are a unique population that is likely to derive from a myeloid precursor cell. DC differentiation from bone marrow precursors is enhanced by the cytokines GM-CSF and tumor necrosis factor-{alpha}. In contrast, it has been proposed that thymic DC and T cells arise from a common stem cell, and that these DC play a specific role in the negative selection of thymic T cells. A number of post-bone marrow differentiation stages can be defined phenotypically and functionally. Undifferentiated DC have very active endocytic pathways, including receptor-mediated endocytosis involving a mannose/ß glucan receptor, and macropinocytosis of soluble antigen. In contrast, later stages of maturation are associated with a decreased ability to take up and process antigen, and increasing expression of major histocompatibility complex, adhesion and costimulatory molecules. Finally, activation of DC for full antigen-presenting cell function can be identified by the expression of CD28 ligands. The inflammatory site in rheumatoid arthritis is a human model of DC differentiation in response to a chronic antigenic stimulus. The features of this DC model are discussed.


   Introduction
Top
 Abstract
 Introduction
Origin
 Differentiation
 Differentiation Stages of DC
 Antigen Processing and DC...
 Conclusion
 References
 
In all species studied, T cells recognize antigens presented on specialized antigen-presenting cells (APC). Dendritic cells (DC) is one of the most potent APC to be described. Lymphoid DC were first recognized by Steinman and Cohn in 1973 as a "novel cell type in peripheral lymphoid organs of mice" [1]. These cells were characterized by their dendritic morphology, low density, exceptional mobility and ability to present antigens to resting T cells. Although first identified in lymphoid organs, cells with these features have since been isolated from many nonlymphoid tissues in both rodents and man, including skin, lung, joint synovium and gastrointestinal tract, as well as peripheral blood (PB) [2–8]. Thus, members of the DC family include epidermal DC, known as Langerhans cells (LC), DC of the afferent lymphatics and thoracic duct (veiled cells), nonlymphoid organ connective tissue DC (interstitial DC) and DC of the lymphoid organs (spleen, lymph node, Peyers patches, thymus and tonsil) known as interdigitating DC [9–14]. The last twenty years have seen tremendous advances in the understanding of the origin, function, differentiation and mechanism of action of DC. This review will address recent advances in the elucidation of the origin and lineage of DC, as well as their differentiation from precursors into mature, fully functional APC.


   Origin
Top
 Abstract
 Introduction
 Origin
Differentiation
 Differentiation Stages of DC
 Antigen Processing and DC...
 Conclusion
 References
 
From transfer studies in rodents and bone marrow transplantation in man, it was demonstrated in vivo that DC originated in the bone marrow [15]. In vitro cultures of rat bone marrow-derived precursors that did not express major histocompatibility complex (MHC) class II molecules were shown to give rise to cells with the morphological and functional features of DC [16]. Similar experiments were subsequently carried out using human bone marrow. Colonies containing both monocytes and DC, as well as typical colony forming units-granulocyte-macrophage (CFU-GM) arose in the cultures [17]. These data suggested that monocytes and DC arose from a common myeloid precursor. The nature of the DC precursor and the growth factors required for development of DC were subsequently elucidated. CD34-expressing stem cells isolated either from human bone marrow or umbilical cord blood were shown to give rise to both monocytes and DC in vitro. Whereas culture in the presence of GM-CSF alone increased the proportion of monocytes proliferating in the cultures, the proportion of DC obtained could be increased by the presence of both GM-CSF and tumor necrosis factor-{alpha} (TNF{alpha}) [18–20]. It has been shown that TNF{alpha} is required early in this system for development of the DC lineage. At least part of the mechanism of action of TNF{alpha} can be explained by the inhibition of granulocyte differentiation in these cultures [21]. In the mouse, as opposed to the human, GM-CSF alone is sufficient for the proliferation and differentiation of DC from their precursors in either bone marrow or PB. Recent studies demonstrate further that the addition of stem cell factor ([SCF], c-kit ligand) augments DC growth from stem cells without altering the developmental commitment induced by TNF{alpha} and GM-CSF [22, 23]. This follows the same general mechanisms previously reported for the action of SCF, in that it synergizes dramatically with specific cytokines to achieve the maximal development of various lineages but has modest effects on pluripotent stem cells [24, 25].

Several lines of experimental evidence indicate that bone marrow-derived DC belong to the myeloid lineage. First, DC and their precursors have been shown to express myeloid lineage markers, including CD13 (aminopeptidase-N) and CD33 in man [6, 26, 27]. Although CD13 is expressed by some nonmyeloid tumor cells, CD33 is expressed uniquely by cells of myeloid lineage [28]. Few such monoclonal antibodies (mAb) are available in rodents. However, the mAb ER-BMDM1 that identified murine macrophages and DC recognizes an antigen with aminopeptidase activity that is likely to be the mouse homologue of CD13 [29]. Second, GM-CSF is the major growth factor required for DC development from bone marrow precursors, as well as for DC differentiation [20, 30, 31]. Furthermore, GM-CSF receptors are expressed abundantly by mouse spleen and skin DC [32]. In contrast, spleen and skin DC lacked T cell receptor and immunoglobulin receptor rearrangements, as well as M-CSF receptors. The normal distribution of DC in op/op mice that lack M-CSF activity is consistent with this [33]. Third, the development of DC in the same bone marrow-derived colonies as monocytes suggests that they derive from a common precursor—the "mono-DC-CFU." A malignant counterpart of the mono-DC-CFU in acute myeloid leukemia was recently described [34]. Although the leukemic precursor cells could be induced to differentiate into DC in the presence of GM-CSF, TNF{alpha} and interleukin 6 (IL-6), G-CSF alone or in combination with GM-CSF could not induce the differentiation of granulocytes from this precursor [34]. The data suggest that the mono-DC-CFU is a distinct post-CFU-GM stage with the inability to produce granulocyte progeny (Fig. 1Go).



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  		Fig. 1. Dendritic cell (DC) differentiation in lymphoid and nonlymphoid organs. Proposed schema for the differentiation of DC from stem cells to mature lymph node DC, based on current experimental evidence. Factors likely to be regulating this process are boxed.

 
Somewhat surprisingly, in the light of the strong evidence for the role of GM-CSF in DC development, GM-CSF knockout mice were found to have normal numbers of monocytes, granulocytes and DC in peripheral tissues [35]. A second analysis noted a modest twofold reduction in peripheral tissue DC numbers, but no alteration in the number of thymic DC in GM-CSF knockout mice. These data suggest that GM-CSF is not essential for the development of myeloid lineage cells, and therefore another CSF or combination of cytokines can replace GM-CSF in its absence. Furthermore GM-CSF may not be necessary at all for thymic DC development. The finding that tissue DC numbers were increased by only twofold in transgenic mice overexpressing GM-CSF whereas thymic DC numbers were normal in these mice (K. Shortman, personal communication) are consistent with these conclusions.

DC in the murine thymus differ from those in other lymphoid and nonlymphoid organs in that they express the lymphoid markers CD8{alpha} and BP-1 (an early B cell marker) [12, 36, 37]. It has been suggested that DC and T cells in the thymus arise from a common stem cell. Thus, purified CD4– bone marrow or CD4dim thymic stem cells, depleted of cells with mature lineage markers, gave rise to DC and T cell progeny, but not monocytes or B cells when injected intrathymically into an irradiated congenic mouse [37]. Stem cells purified from bone marrow, but not thymus, gave rise to DC within both spleen and thymus after i.v. injection [37]. The development of T cells and thymic DC in parallel from a common precursor implies that thymic T cells will be negatively selected by self-antigen presented predominantly by newly differentiating thymic DC, rather than by exogenous antigen sequestered in the periphery and brought to the thymus by circulating DC. In this regard, it is noteworthy that murine thymic DC synthesize and express CD8{alpha}. Since CD8 has been shown to be involved in the negative signaling of thymic T cells through their MHC class I molecules [38], it has been proposed that thymic DC might therefore act as "veto cells" for negative selection [36].

A similar DC population has not been isolated from human thymus. Moreover, human thymic DC appear to express similar markers to those of human PB DC in that they are CD1–CD8–CD4hilin– and MHC class II+ [39]. Although they are CD14–, they may be myeloid lineage-derived in that they can be infected with myelotropic rather than lymphotropic strains of HIV (K. Shortman, personal communication). In summary, current data suggest that in the mouse, multipotential bone marrow stem cells can give rise to DC and T cells within the thymic microenvironment. Although DC outside the thymus also appear to arise from the same precursor and belong to the myeloid lineage, murine thymic DC have a particular lineage relationship with T cells that seems to be distinct from that of other DC and is perhaps imposed by the thymic microenvironment. In man, the various T lineage markers expressed by DC, including CD4, CD1, CD2 and CD5, suggest a lineage relationship between T cells and myeloid cells [26, 39–41]. However, the exact nature of the relationship between T cells and DC, and the impact of the tissue microenvironment in which the DC develops, are as yet unclear.

Finally, the role of the relB subunit of the NF-{kappa}B complex has been recently addressed in the context of DC development. The expression of relB by DC was demonstrated in adult murine spleen, lymph node and thymus, embryonic murine thymus and neonatal spleen, as well as in inflammatory infiltrates in the pancreatic islets of mice with autoimmune diabetes [42, 43]. Furthermore, mice with a disruption of the relB gene lacked a thymic medulla and had impaired splenic APC function, delayed-type hypersensitivity responses, and reduced numbers of thymic but not resting skin DC [42, 44]. Thus, the expression of relB seems to correlate with DC differentiation, whereas disruption of relB expression blocks the development of DC. This suggests that relB regulates expression of genes, possibly MHC class II, associated with the differentiated DC phenotype [43]. The implication of members of the rel family of transcription factors in lymphoid malignancies further suggests their role in cell growth and differentiation. For example, the oncogene v-rel was identified as the transforming viral gene that causes avian B cell lymphomas [45]. Of interest, v-rel estrogen receptor-transformed chicken bone marrow cells that had undergone estrogen antagonist-induced differentiation arrest were found to differentiate either into antigen-presenting DC or granulocytes, depending upon the culture conditions [46]. These data further support the idea that DC and granulocytes arise from a common myeloid precursor, and that their differentiation might be influenced by similar rel family transcriptional factors.


   Differentiation
Top
 Abstract
 Introduction
 Origin
 Differentiation
Differentiation Stages of DC
 Antigen Processing and DC...
 Conclusion
 References
 
Following their egress from the bone marrow, a number of DC differentiation stages can be phenotypically and functionally defined. As mentioned above, CD34+ stem cells can give rise to DC in the presence of appropriate cytokines in bone marrow or in vitro. Human PB contains approximately 0.1% CD34+ cells, and it has therefore been hypothesized that DC differentiation from such precursors might also take place in tissues outside the bone marrow in the presence of the appropriate cytokines [20]. Direct evidence supporting this conclusion has yet to be obtained. It has recently been demonstrated that the adherent fraction of human PB also contains a proliferating DC precursor [47]. Although the exact nature of this precursor is unknown, it appears unlikely to be a CD34+ stem cell since these cells are nonadherent. DC can be generated from adherent PB mononuclear cells in the presence of GM-CSF and IL-4 [47, 48]. It is thought that IL-4 is required to suppress the development of monocyte progeny in these cultures.

The earliest post-bone marrow committed DC precursors have been shown to lack MHC class II antigen expression. Such MHC class II– DC precursors have been demonstrated in mouse thymus, bone marrow, neonatal rat lung, neonatal epidermis and human adult and fetal blood [49–53]. In the rat fetal airways, cells expressing the rat DC-specific marker, OX62, but lacking MHC class II expression are found in high numbers. They are gradually replaced by MHC class II+ DC throughout infancy and the post-weaning period [53].

MHC class II+ circulating DC precursors have been best characterized in adult human blood. Utilizing two different purification methods, two populations of PB DC precursors have been identified—the first by the expression of CD33 and low to negative expression of CD14, and the second by the absence of T cell, B cell, NK cell and monocyte lineage marker expression (lin–) but the expression of HLA-DR [6, 40]. These precursor populations were similar morphologically and phenotypically, in that they were round in shape, and expressed relatively low levels of MHC and adhesion molecules. However, the CD33+CD14dim precursors spontaneously differentiated into functionally mature DC in vitro, whereas the lin–DR+ precursors were dependent both morphologically and functionally on secreted cytokines for their differentiation [6, 40]. These data suggested that several DC precursor subsets might circulate in PB, at least one of which is dependent upon monocyte-derived cytokines for its maturation. This conclusion was subsequently confirmed by the isolation of a phenotypically and functionally mature DC subset found in circulating PB. The cells could be identified as CD33brightCD14dim. In contrast, CD33dimCD14dim cells were phenotypically and functionally precursor DC [52]. A very similar mature DC population was identified as lin–CD11cbright [27]. In contrast to the PB DC precursors which constituted approximately 1% of peripheral blood mononuclear cells (PBMC), the smaller mature DC subset constituted approximately 0.1% of PBMC. Mature DC purified by either method spontaneously differentiated in vitro into functional DC. The DC maturation process therefore appears to be associated with the ability of the cells to secrete autocrine growth factors allowing their spontaneous differentiation in vitro.

Higher levels of adhesion and MHC molecules were expressed by the mature PB DC than by precursor DC. However, neither PB DC population constitutively expressed the costimulatory molecules B7-1 (CD80) or B7-2 (CD86) [27, 52]. It therefore appears likely that a further signal is required for CD80/CD86 expression and full functional activity of both circulating precursor and mature DC subsets. This final signal is required for a specific stage of differentiation or "activation" of DC associated with expression of CD80/CD86 and the functional capacity to stimulate resting T cells. In both human and mouse, CD86 (B7-2) has been demonstrated to be a more significant costimulatory molecule than CD80 (B7-1) because of its greater expression by activated DC. This has been confirmed by blocking studies in which only anti-CD86 but not anti-CD80 mAb block DC-stimulated assays of antigen presentation. Moreover, to date the blocking studies have not suggested that DC are likely to express a third CD28/CTLA4 ligand. The expression of CD86 by DC can be upregulated by the cytokines GM-CSF and interferon-{gamma}, as well as by engagement of CD40 by membrane-bound or soluble CD40 ligand [54–57]. In normal murine tissue, CD86/B7-2 appears to be expressed specifically in lymph node, and not nonlymphoid tissue [58]. We have found CD86 expression by HLA-DR and DQ+ DC in a perivascular location in the inflamed synovial tissue of patients with rheumatoid arthritis (RA) but not in osteoarthritis synovium. CD86 expression has been noted similarly in inflamed skin in the autoimmune skin disease, psoriasis, but not in normal human skin [59]. Taken together, the data indicate that the costimulatory molecule CD86/B7-2 is not expressed by DC as part of the normal differentiation process until the cells are activated by a specific physiological stimulus.

The site of maturation of the CD33brightCD14dim PB DC subset is as yet unknown. It is possible that maturation of PB DC precursors takes place in the spleen, or in other tissues, and that some mature DC then re-enter the circulation rather than migrate to lymph nodes. If this were true, one might expect an increased proportion of mature circulating DC in the context of an ongoing immune response in peripheral tissue. We examined this question in RA, in which there is an ongoing immune response in the joint. Steady state proportions of precursor and mature PB DC subsets were no different in RA from those of normal subjects, arguing against a direct relationship between tissue DC differentiation in the context of antigen presentation and the entry of differentiated DC into the circulation.

Nonlymphoid uninflamed tissue DC, including skin, lung, cornea and gut DC, are morphologically dendritic, but phenotypically relatively immature. Their dendritic morphology is likely to result from interaction with tissue matrix or factors produced in tissue [60]. GM-CSF has been shown to be essential for the upregulation of the function of DC from these tissues in vitro [31, 61–63]. This functional upregulation is associated with differentiation phenotypically. Thus, GM-CSF leads to upregulation of MHC class I and II molecules, as well as CD80 and CD86 expression by mouse and human LC [59, 64, 65]. These in vitro experiments are likely to recapitulate the in vivo differentiation of DC in the context of antigen uptake and migration to lymph node [66]. Thus, DC purified from lymphoid tissue, such as tonsil, are fully functional and express markers of DC differentiation and activation, including MHC class II and adhesion molecules, CD80 and CD86 [58, 67].


   Differentiation Stages of DC
Top
 Abstract
 Introduction
 Origin
 Differentiation
 Differentiation Stages of DC
Antigen Processing and DC...
 Conclusion
 References
 
A number of markers has been found to be useful to define the differentiation of human DC. CD33 expression parallels DC maturation both in vitro and in vivo [52, 68]. As discussed above, DC appear to arise ultimately from MHC class II– precursors, and HLA-DR and DQ expression increases with DC differentiation and maturation [6, 52]. CD11c and CD45RO have been found to be expressed by the mature PB DC subset, as well as by a proportion of CD33dimCD14dim precursor DC. By contrast, a recently described marker, CMRF-44, was only expressed by the mature PB DC subset. Utilizing the rheumatoid synovium as a model of a site of an ongoing immune response in which DC are differentiated and activated, we therefore examined the expression of these markers. Approximately 40% of synovial fluid (SF) DC expressed high levels of CD33 and the rest were CD33dim, but all SF DC expressed CD11c and CD45RO. The CD33bright SF DC also expressed CMRF-44, and a subset of these expressed CD86. The data suggest a progression of differentiation steps towards fully activated, functional DC (Fig. 2Go). Thus, after the expression of MHC class II, CD11c and CD45RO are relatively early markers of differentiation. CMRF-44 is expressed subsequently and, finally, CD86. In support of this conclusion is the expression CMRF-44 by human tonsil DC.



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  		Fig. 2. Schema for dendritic cell (DC) maturation in rheumatoid arthritis. The study of DC in the inflammatory site provides insight into the differentiation and activation of DC in response to chronic antigen and cytokine signals. Although the expression of DC differentiation and activation markers by putative bone marrow precursors has not been fully characterized, at least two subsets of circulating DC have been identified: a large precursor pool and a much smaller differentiated population. Neither of these subsets are activated, as identified by CD86 expression. In contrast, DC found at the inflammatory site are enriched in the differentiated subset and some are also activated. The activated DC in the synovium phenotypically resemble tonsillar lymph node DC.

 
CD83 is a member of the immunoglobulin superfamily of as yet unknown function that is expressed by in vitro activated PB DC and lymphocytes, a subset of skin LC, and interdigitating DC of lymphoid organs [41, 69]. Thus, PB DC prepared by incubation and density gradient sedimentation of PB non-T cells expressed CD83. These DC also constitutively express CD86 and low levels of CD80, consistent with an activated phenotype. Potent APC function was markedly enriched in the CD83+ fraction [41]. CD83 has been reported to be absent on freshly-isolated PBMC [41]. Similarly, we have found that in contrast to the aforementioned markers, CD83 is expressed neither by freshly-isolated CD33dimCD14dim DC precursors nor by CD33brightCD14dim mature DC. Therefore, like CD86, CD83 appears to be expressed by mature, in vitro activated PB DC, but not by circulating DC precursors.


   Antigen Processing and DC Differentiation
Top
 Abstract
 Introduction
 Origin
 Differentiation
 Differentiation Stages of DC
 Antigen Processing and DC...
Conclusion
 References
 
Although it was originally believed that DC had relatively poor fluid-phase endocytic activity, several lines of evidence now support the conclusion that DC are very endocytically active. First, a flow cytometric assay of traffic through late endosomes demonstrated that mouse spleen DC were as endocytically active as B lymphoma or activated splenic B cells [70]. Second, freshly-isolated LC and splenic DC were able to phagocytose bacteria and inert particles but not opsonized sheep RBC. In particular, uptake of the yeast cell wall derivative, zymosan, was mediated by a mannose/ß glucan receptor [71]. Similarly, bone marrow-derived DC progenitors were found to internalize Calmette-Guerin bacillus (BCG) as well as latex particles [72]. Third, human blood DC derived by culture in GM-CSF and IL-4 have been shown to take up a high level of soluble antigen by a process known as macropinocytosis. Macropinocytosis is constitutive in these DC and allows continuous internalization of large volumes of fluid [73]. Human DC can also capture antigens by means of a mannose receptor that delivers a large number of antigens to the cell in successive rounds. The likely murine homologue of this receptor, DEC-205, has been cloned. It is recognized by the DC-specific mAb, NLDC-145. However, more sensitive anti-DEC-205 antibodies also detect low level expression by B cells [74, 75].

Downregulation of the phagocytic activity of cultured DC and LC has been noted [76, 77]. This appears to be mediated at least in part by downregulation of the mannose/ß glucan receptor during maturation of LC in culture [71]. However, loss of the acidic early endosomes has also been noted in cultured LC, suggesting that changes in the vacuolar system involved in antigen processing also occur upon differentiation [78]. In contrast to the low level of expression of MHC class II molecules in fresh LC, class II is synthesized at high levels. Cultured LC express high levels of MHC class II molecules but downregulate class II biosynthesis. Thus, newly synthesized MHC class II molecules may be important for effective antigen presentation by fresh LC. Although some previous studies demonstrated active fluid-phase endocytosis and traffic through early and late endosomes in cultured DC [79, 80], a recent analysis of fresh and cultured LC demonstrated small subpopulations of immature LC within the cultured LC preparations that were primarily responsible for antigen processing by the cultured cells [81].

In summary, undifferentiated DC, such as resting tissue LC, likely internalize the antigen to which they are exposed, transport it to an acidic endosomal compartment where it is degraded, and the derived peptides meet newly synthesized class II MHC molecules in MHC class II enriched compartments. The peptide-MHC complex may then be expressed in high density on the cell surface as the DC differentiates. Once differentiated, however, antigen processing may be diminished because of a reduction in acidic endosomes, downregulation of MHC class II synthesis and of expression of invariant chain and the mannose receptor/DEC-205 [71, 76, 78]. This would result in a reduction of MHC-bound peptide turnover in mature DC and sequestration of antigenic peptides by the DC, as demonstrated by antigen-bearing LC migrating from skin to lymph node [82]. Following antigen uptake, DC migrate rapidly to lymph nodes, where they initiate the primary immune response [4, 82]. TNF{alpha} is the principal cytokine implicated in stimulating the migration of LC to draining lymphatics [83].

Little is known of the fate of DC after they have carried out their antigen-presenting function in the lymph node. Early work suggested that, after encountering antigen, DC can become targets for NK cell-mediated lysis [84]. Apoptosis by DC has recently been addressed. Mature LC that had migrated from human epidermis were found to undergo spontaneous apoptosis in vitro [56]. The apoptotic cells could be rapidly ingested by macrophages in vitro. Apoptosis could be inhibited in these cultures by the addition of TNF{alpha} or soluble CD40 ligand. By contrast, IL-10 increased the rate of DC death [56]. These data are consistent with previous studies in which the viability of mouse LC was demonstrated to be improved by addition of TNF{alpha} [56]. Similarly, membrane-bound CD40 ligand improved the viability of human blood DC in vitro [55]. Taken together, these data support the conclusion that DC rapidly undergo apoptosis either in the absence of factors that maintain their viability, or appropriate stimulatory molecules. In vivo estimates of DC life span vary according to the method used, as well as the species and organ studied. They range from three days to four weeks, and perhaps longer in the skin [1, 15, 85, 86]. DC have been found to be enriched in the chronic tissue inflammation associated with a number of human autoimmune diseases and animal disease models [8, 87–90]. However, no study as yet has examined whether this is the result of local DC proliferation, greater DC chemoattraction, reduced migration from the tissue to draining lymph nodes, or reduced rates of apoptosis of DC within the inflamed site. These questions are clearly of great importance for the understanding of the role of DC in the pathogenesis of the organ inflammation of autoimmune disease. The production of factors such as GM-CSF and TNF{alpha} at the site of inflammation implies that a number of mechanisms, including local proliferation and apoptosis, may play a role in the maintenance of large numbers of DC locally.


   Conclusion
Top
 Abstract
 Introduction
 Origin
 Differentiation
 Differentiation Stages of DC
 Antigen Processing and DC...
 Conclusion
References
 
The last five years have been very productive in the contribution of knowledge of DC differentiation from the cradle to the grave. The development of techniques for the in vitro culture of large numbers of DC derived from bone marrow or blood-derived precursors has opened many clinical possibilities for vaccination of antigens derived from pathogens and tumors. Finally, knowledge of the factors involved in the differentiation of DC into effective APC should allow specific intervention in this process in clinical settings such as autoimmune disease.


   Acknowledgments
 
This project was supported by grants AR09989 and AR39169 from the National Institute of Arthritis, Musculoskeletal and Skin Diseases, the Arthritis Foundation of Queensland, the Arthritis Foundation of Australia and the Royal Australasian College of Physicians.


   References
Top
 Abstract
 Introduction
 Origin
 Differentiation
 Differentiation Stages of DC
 Antigen Processing and DC...
 Conclusion
 References
 

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accepted for publication October 30, 1995.




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