ENCOUNTER WITH PROSTATE CANCER: July 2010

Dendritic cells (I) : biological functions

SCIENTIFIC REVIEW
Dendritic cells (I) : biological functions

S. SATTHAPORN* and O. EREMIN*#
*Section of Surgery, E Floor, West Block, Queen's Medical Center, University of Nottingham, Nottingham U.K. and #Research and Development , United Lincolnshire NHS Trust, Lincoln, U.K.

Introduction

Dendritic cell development

Functional differences between the different DC subsets.

Migration and functional properties of dendritic cells
Maturation and function of dendritic cells

DC death (apoptosis)

Dendritic cell distribution

References

Dendritic cells (DCs) are potent antigen presenting cells (APCs) that possess the ability to stimulate naïve T cells. They comprise a system of leukocytes widely distributed in all tissues, especially in those that provide an environmental interface. DCs posses a heterogeneous haemopoietic lineage, in that subsets from different tissues have been shown to posses a differential morphology, phenotype and function. The ability to stimulate naïve T cell proliferation appears to be shared between these various DC subsets. It has been suggested that the so-called myeloid and lymphoid-derived subsets of DCs perform specific stimulatory or tolerogenic function, respectively. DCs are derived from bone marrow progenitors and circulate in the blood as immature precursors prior to migration into peripheral tissues. Within different tissues, DCs differentiate and become active in the taking up and processing of antigens (Ags), and their subsequent presentation on the cell surface linked to major histocompatibility (MHC) molecules. Upon appropriate stimulation, DCs undergo further maturation and migrate to secondary lymphoid tissues where they present Ag to T cells and induce an immune response. DCs are receiving increasing scientific and clinical interest due to their key role in anti-cancer host responses and potential use as biological adjuvants in tumour vaccines, as well as their involvement in the immunobiology of tolerance and autoimmunity.

Keywords: antigens, dendritic cells, development, distribution, functions, maturation, T cells

J.R.Coll.Surg.Edinb., 46, February 2001, 9-20

INTRODUCTION

Dendritic cells (DCs), originally identified by Steinman and his colleagues (1972) represent the pacemakers of the immune response.1 They are crucial to the presentation of peptides and proteins to T and B lymphocytes and are widely recognized as the key antigen presenting cells (APCs). They are critical for the induction of T cell responses resulting in cell-mediated immunity (CMI). The T cell receptors (TCRs) on T lymphocytes recognize fragments of antigens (Ags) bound to molecules of the major histocompatibility complex (MHC) on the surfaces of APCs. The peptide binding proteins are of two types, MHC class I and II, which interact with and stimulate cytotoxic T lymphocytes (CTLs) and T helper cells (Ths), respectively. On entry into APCs, Ags are processed, spliced into peptides in the cytosol and then reexpressed on the cell surface linked to MHC proteins. When bound to MHC class I molecules, CTLs are generated and activated and cells in tissues expressing the Ags (e.g. virus infected cells, cancer cells) are recognised and destroyed. Antigens reexpressed on the cell surface linked to MHC class II molecules interact with Th cells which when activated have profound immune-regulatory effects.2 Thus, DCs play a key role in host defenses and a crucial role in putative anti-cancer immune responses.

DENDRITIC CELL DEVELOPMENT

Introduction

An important advance in DC biology, within the past few years, has been the ability to propagate in vitro large numbers of DCs, using defined growth factors. One of the most important findings is that DCs are not a single cell type, but a heterogeneous collection of cells that have arisen from distinct, bone marrow-derived, hematopoietic lineages.3-7 To date, at least three different pathways have been described. The emerging concepts are that each pathway develops from unique progenitors, that particular cytokine combinations drive developmental events within each pathway and that cells developing within a particular pathway exhibit distinct specialized functions.3-7

The ability to propagate DC subtypes, at various stages of development in vitro, from early progenitors has been critical in assessing the developmental and functional characteristics of DCs. Together with in situ histochemical analyses and genetically modified animal models, in vitro studies have shown that the earliest DC progenitors/precursors are released from the bone marrow and circulate through the blood and lymphoid organs ready to receive differentiation signals.4-6

Several studies have been carried out suggesting that there are different pathways for the formation of mature DCs from CD34+ or other primitive progenitors. Each pathway differs in terms of progenitors and intermediate stages, cytokine requirements, surface marker expression and, probably most importantly, biological function.

Lymphoid-related DC pathway

The close lineage relationship of DCs and monocytes has been challenged in recent years by the findings of several groups who have described the development of DCs and lymphoid cells from the same precursors. The term lymphoid DC is meant to describe a distinct DC subtype that is closely linked to the lymphocyte lineage.

Initially described in the mouse, the term ‘lymphoid’ refers to several features that suggest a precursor in common with T cells. This pathway appears to lack a number of characteristics found in myeloid cells, in particular, lack of defined surface phenotypes-CD11b, CD13, CD14, and CD33. 7 In blood, the lymphoid precursors may be the CD4+ CD11c+ ‘plasma-like cell’. There is now some evidence that an equivalent lymphoid lineage DC exists in humans.7-12 Lymphoid DCs may also arise from progenitors that also have the potential to mature into T and natural killer (NK) cells.7-12 Such progenitors are distributed in the thymus and in the T cell areas of secondary lymphoid tissues.5,7-12 Lymphoid DCs may develop from thymic progenitors when stimulated with Interleukin 3 (IL-3), but not granulocyte macrophage colony-stimulating factor (GM-CSF), and from lymphoid precursors in human tonsil treated with CD40 ligand (CD40L).7,10 More recently, IL-2 and IL-15 have been shown to drive NK cell-associated (IL-2R+) DCs from CD34+ progenitors.11,12

A variety of functions have been attributed to lymphoid DCs. They promote negative selection in the thymus (possibly by inducing fas-mediated apoptosis) and are costimulatory for CD4+ and CD8+T cells.7, 13-15 More recently, lymphoid-like DCs derived from human progenitors have also been shown to preferentially activate the Th2 response.14 Because of their capacity to induce apoptosis and their role in eliminating potentially self-reactive T cells, it has been suggested that lymphoid DCs primarily mediate regulatory rather than stimulatory immune effector functions.7, 14, 16

In the human bone marrow, Galy et al (1995) identified a subset of progenitor cells defined by the phenotype CD34+ CD38+ Thy-1- CD10+. The latter, when cultured under appropriate conditions, were capable of giving rise to T, B, NK and DCs but not to myeloid cell types.8 Progenitors with a similar phenotype but lacking CD10 expression could give rise to myeloid cells and more prolonged thymopoiesis suggesting that acquisition of CD10 corresponded to a maturation step and commitment to T, B, NK and DC lineages. Similarly, a CD34+ Thy-1- but CD38dim foetal thymic precursor gave rise to T, NK and DCs but not other (myeloid) lineages, whilst the more mature CD34+ CD38+ thymic precursor was shown to have less DC potential.17 These results suggest that thymic DCs and thymocytes are derived from a common precursor that migrates to the thymus prior to lineage commitment and terminal differentiation. Lymphoid DCs include those in the thymic medulla and many of the DCs in the T cell areas of all peripheral lymphoid organs. Dendritic cells in the latter T cell areas, however, are heterogeneous and include other types of DCs, for example, sentinel and migratory DCs that have brought Ags from peripheral tissues. Lymphoid DCs in T cell areas have the capacity to regulate self-reactive T cells, for example, by the production of IL-10 or other cytokines, or to delete them, for example, by induction of apoptosis by a member of the tumour necrosis factor (TNF) family like fasL18 or CD30L.19

Myeloid DC pathway: CD34+ haemopoietic progenitors

The myeloid pathway is distinguished by a development stage in which there is expression of certain features associated with phagocytes. Studies with multipotent CD34+ progenitors and peripheral blood mononuclear cells (PBMCs) have described different DC pathways, both associated with the myeloid lineage.

The skin contains a prominent supply of tissue DCs, termed Langerhan cells (LCs), which have typical DC morphology and contain characteristic Birbeck granules (BGs), seen on electron microscopy or by staining, using a specific monoclonal antibody (Mab).20 Evidence from murine bone marrow transplantation studies suggests that LCs are derived from the donor and that they are presumably of myeloid origin.21 In the rat, Bowers and Berkowitz (1986) demonstrated DCs in myeloid colonies in semi-solid cultures of Ia- bone marrow precursors and this was noted also in clonal assays of human bone marrow.22,23 More recent studies, using methylcellulose culture assays of human bone marrow or PBMCs, identified colonies both of pure DCs and also of mixed dendritic/macrophage cell types. Colonies were observed after 14 days of culture when stimulated by leukocyte conditioned medium.24 The resultant cells resembled LCs in their gross morphology and ultrastructure though they lacked the BGs typical of skin LCs. They were CD34+, had high levels of HLA-DR but, unlike the macrophages from the same cultures, were also HLA-DQ+ and lacked both a strong non-specific esterase expression and the monocyte-associated cytoplasmic antigen CD68. Most characteristically, they strongly expressed CD1a+ and their DC phenotype was confirmed by high allostimulatory activity in mixed leukocyte reactions (MLRs)-greater than either macrophages or even fresh blood DCs.

Myeloid DC pathway: PBMCs and CD14+cells

There is considerable evidence from culture studies for a close developmental relationship between DCs and cells of the monocyte/macrophage lineage.6,25 Adherent PBMCs are enriched for monocytes, and this fraction may develop a LC phenotype and function if cultured in the presence of foetal calf serum (FCS).26,27 Further, amongst the PBMCs, only purified monocytes are capable of expressing the LC marker CD1a if cultured in GM-CSF.28 The cytokines required for the in vitro production of DCs from the adherent fraction of PBMCs were first documented by Romani et al (1994) and by Sallusto and Lanzavecchia (1994).29,30 They demonstrated that cultures of PBMCs in GM-CSF and IL-4 produced cells that were CD1a+ CD14- and capable of Ag uptake and processing, the typical profile of immature DCs. Yields of up to 8x106 DCs were obtained from 40 ml of blood.29,30 The possibility that the DCs were derived from contaminating progenitor cells had been excluded by using highly purified CD14Bright monocytes31 and the absence of cellular proliferation in culture.20, 32, 33 Although the resulting cells resembled immature DCs they were atypical because of the presence of lysozyme, myeloperoxidase, non-specific esterase and their lack of CD83.20, 21, 31 In some studies, further differentiation into fully mature DCs could be induced by exposing these cells to a or CD40.21 This final maturation was characterised by downregulation of the ability to take up and process Ag whilst CD54, HLA-DR, CD83 and CD80 expression increased in parallel with the Ag presenting function.21 Rozenwaig et al. (1996) demonstrated a well ordered phenotypic evolution of DC precursors via CD13Low progenitors to CD13High CD1a- and then CD13High CD1a+ intermediates that also expressed variable levels of CD14.23 Using a similar approach, two pathways of DC maturation from cord blood CD34+ progenitors were identified. After 5 days in culture with GMCSF, SCF and TNF-a, cells were sorted into either CD14+CD1a- or CD14-CD1a+ populations (see Table 1).3

Table 1: Comparison of the different developmental pathways of DCs of myeloid origin
Derived from CD14+CD1a - Derived from CD14-CD1a+
Related to interstitial and/or circulating blood DCs Related to epidermal DCs (LCs)
Nonspesific esterase activity; complement receptors (CD11b, CD15b) Intracellular BGs, Lag molecules, E-cadherin
Phagocytic properties
CD68+ and express coagulation factor XIIIa Lack CD68 and factor XIIIa expression
TNF, GM-CSF and IL-13 or IL-4 induce maturation TGF-b induces maturation

FUNCTIONAL DIFFERENCES BETWEEN THE DIFFERENT DC SUBSETS

Although functional differences exist between the myeloid and lymphoid DCs, functional segregation within the myeloid DC lineage system also exists. Several in vitro studies have shown that CD14-derived DCs prime T cells to preferentially activate Th1 responses and IL-12 appears implicated in this process.34, 35 CD14-derived DCs from CD34+ progenitors, but not CD1a-derived DCs, also activate naive B cells to secrete IgM in the presence of CD40L and IL-2.36 In psoriasis and atopic asthma, distinct DC subtypes activate either Th1 or Th2 responses, respectively supporting the existence of pathophysiological associations between DC subtypes and Th cell subsets.37, 38 This raises the possibility of redirecting tissue destructive T cell responses to nondamaging T cell responses in certain diseases. Additional observations indicate that CD14-derived DCs are increased in rheumatoid arthritis as it is predominantly associated with an inflammatory Th1 response.39-41

The thymic DCs expressing CD8a+ appear to be functionally different from CD8a- DCs in that they express Fas-L and can induce T cell apoptosis. Thymic DCs are also far less efficient at inducing T cell IL-2 cytokine production.18 Thus, CD8a+ DCs may have regulatory properties, whereas CD8a- DCs seem to exert T cell stimulatory function. More functional studies have to be performed in order to fully evaluate the pro B lymphocyte DCs, and whether the pro B lymphocyte-derived DCs have unique functions that are not exhibited by the thymic DCs, remains to be elucidated.

It is clear from the forgoing discussion that DCs may develop from a myeloid or lymphoid lineage. The myeloid pathway of differentiation gives rise to DCs that home to peripheral tissues to take up and process exogenous Ags prior to migrating to the secondary lymphoid tissues to present Ags to naïve T cells. Thymic DCs, on the other hand, perform a very different function being involved in the presentation of self-Ag to developing thymocytes and, hence, the subsequent deletion of autoreactive T cells. It would be appropriate for the precursors of thymic DCs to migrate to the thymus in an immature form and undergo development exposed only to self-Ag within the thymus.42 Thus, the existence of alternative developmental pathways would be in keeping with the different functions of DCs in different tissues.

Further studies have revealed that CD8a+ DCs were at least equivalent to CD8a- DCs in stimulating both CD4 and CD8 responses in vivo and in vitro. A surprising recent finding is that, CD8a+ DCs, but not CD8a- DCs, produce significant levels of IL-12 and prime Th1 T cell response.43-46 Thus, the immunoregulatory potential of DCs may depend less on ontology than on recent activatory or downregulatory stimuli. Appropriate induction of T cell tolerance or activation would be ensured by allowing DC behavior to be influenced by environmental signalling at the time of Ag encounter.

MIGRATION AND FUNCTIONAL PROPERTIES OF DENDRITIC CELLS

Myeloid DCs are derived successively from proliferating progenitor cells and non proliferating precursors (especially monocytes). They migrate to and reside as immature DCs at body surfaces and interstitial spaces. Immature DCs have abundant MHC II products within intracellular compartments (MIICs) and respond rapidly to inflammatory cytokines and microbial products to produce mature T cell stimulatory DCs with abundant surface MHC II proteins (see Table 2 and 3); eventually leading to apoptotic death. Some researchers have reported that the Flt-3 ligand can mobilize DCs from proliferating progenitors in humans.47 The immature DCs have many MIICs but require a maturation stimulus to irreversibly differentiate into active T cell stimulatory, mature DCs. Randolph (1998) has described an in vitro system involving monocytes reverse transmigrating across an endothelial monolayer that offers a possible explanation.48 This type of situation would occur when cells move from tissues to afferent lymph. It is possible that veiled DCs in lymph originate from monocytes in tissue that interact with the lymphoid endothelium to acquire the properties of immature DCs. If the monocytes also phagocytose particles before they reverse transmigrate, then the cells become typical mature DCs; the process occurs within 48 hours. The cells posses several markers (p55, DC-LAMP and CD83) that are expressed by mature DCs but are weak or absent in other leukocytes.49-51 Dendritic cells that have matured from monocytes in this in vitro system also express very high levels of surface MHC class II and CD86 and, in complete contrast to monocytes, have lost CD14, CD32 and CD64, all within 48 hours of culture (see Tables 2 and 3).

Table 2: Characteristics of immature dendritic cells
Characteristics of immature dendritic cells

* High intracellular MHC II in the form of MIICs
* Expression of CD1a
* Active endocytosis for certain particulates and proteins; presence of FcgR and active phagocytosis
* Deficient T cell sensitization in vitro
* Low/absent adhesive and costimulatory molecules (CD40/54/58/80/86)
* Low/absent CD25, CD83, p55, DEC-205, 2A1antigen
* Responsive to GM-CSF, but not M-CSF and G-CSF
* Maturation inhibited by IL-10

Table 3: Characteristics of mature dendritic cells
Characteristics of mature dendritic cells

* Cell shape: Numerous processes (veils, dendrites)
* Motility: Active process formation and movement
* Antigen capture: Macrophage mannose receptor, DEC-205 receptor
* Antigen presentation: High MHC class I and II expression
* Abundance of molecules for T cell binding and costimulation, (e.g. CD40, CD54/ICAM-1, CD58/LFA-3, CD80/B7-1 and CD86/B7-2)
* Cytokines: Abundant IL-12 production; resistance to IL-10 DC-restricted molecules: p55, CD83, S100b
* Absence of macrophage-restricted molecules and function: CD14, CD115/c-fms/M-CSF responsiveness, low CD68, myeloperoxidase and lysozyme, bulk endocytic activity (pinocytosis, phagocytosis)
* Stability: No reversion/conversion to macrophages/lymphocytes

Another source of DCs is the immature LC present within the epidermis. LCs are the prototype immature DC, as revealed by Schuler and Romani (1985 and 1989).52, 53 Immature DCs lack or have low levels of several important accessory molecules that mediate binding and stimulation of T cells -CD40, 54, 58, 80 and 86.52, 53 The MHC II molecules are primarily within the cell in MIICs that coexpress lysosomalassociated membrane proteins and HLA-DM or H-2M.54-56 Randolph et al (1998) have reported that human LCs express high level of MDR-1, a multi-drug resistance receptor. LC migration in vitro from skin organ cultures is blocked by anti-bodies or drugs (verapamil, reserpine) that block MDR-1 or P-glycoprotein.57 There are at least 2 mdr genes, and one controls the extrusion of leukotrienes. Also, recent studies show that specific chemokines and chemokine receptors direct the movements of immature and mature DCs; in particular the inflammatory chemokines macrophage inflammatory protein (MIP)-1a and MIP-3a for mobilizing immature DCs and constitutive lymphoid chemokines (MIP-3b or EBI1-ligand chemokines (ELC), 6C-kine or secondary lymphoid tissue chemokines (SLC), for directing mature DCs to T cell areas in secondary lymphoid compartments.58-60

MATURATION AND FUNCTION OF DENDRITIC CELLS

In most tissues, DCs are present in a so-called ‘immature’ state and are unable to stimulate T cells. Although these DCs lack the requisite accessory signals for T cell activation, such as CD40, CD54, CD80 and CD86, they are extremely well equipped to capture Ags in peripheral sites. Once they have acquired and processed the foreign Ags, they migrate to the T cell areas of lymph nodes (LNs) and the spleen, undergo maturation and stimulate an immune response.

Immature DCs have several features that allow them to capture Ag. Firstly, they can take up particles and microbes by phagocytosis.61, 62 Secondly, they can form large pinocytic vesicles in which extracellular fluid and solutes are sampled; a process called macropinocytosis.55 And thirdly, they express receptors that mediate adsorptive endocytosis, including lectin receptors like the macrophage mannose receptor and DEC-205, as well as Fcg and Fce receptors.30,63

Macropinocytosis and receptor-mediated Ag uptake is very efficient, requiring picomolar and nanomolar concentration of Ag, much less than the micromolar levels typically required by other APCs. However, once DCs have captured Ags, which also provide the signal to mature, their ability to capture more Ag rapidly declines.

The captured Ags enter the endocytic pathway of the cell. In macrophages, most of the protein substrates are directed to the lysosomes, organelles with only a few MHC class II molecules, where the Ags are completely digested into amino acids. By contrast, DCs are able to produce large amounts of MHC class II-peptide complexes. This is due to the specialized, MHC class II rich compartments (MIICs) that are abundant in immature DCs.54, 64, 65 During maturation of DCs, MIICs convert to non-lysosomal vesicles and discharge their MHC-peptide complexes on to the cell surface.65, 66

Once primed, the DCs migrate to secondary lymphoid compartments (e.g. LNs) to present Ag-peptide complexes to naïve CD4+ T cells and CD8+ cytotoxic T cells. Following education by Ag-loaded DCs in LNs, naïve CD4+ T cells differentiate into memory helper T cells, which support the differentiation and expansion of CD8+ CTLs and B cells. Helper T cells exert anti-tumour activity indirectly through the activation of important effector cells such as macrophages and CTLs, which are capable of eradicating tumour cells or virus-infected cells directly. DCs are able also to present Ags via the exogenous class I presentation pathway.67,68 A dedicated peptide transporter translocates these peptides from the cytosol to the endoplasmic reticulum, where they bind to class I molecules. The peptide-bound MHC class I complexes migrate to the cell surface where they are displayed for T cells. This interaction generates CTLs, which have the capacity to eliminate virally infected cells and tumour cells.

It is clear that the maturation of DCs is crucial for the initiation of immunity. This process is characterized by reduced Ag-capture capacity and increased surface expression of MHC and co-stimulatory molecules. However, the maturation of DCs is completed only upon interaction with T cells. It is characterized by loss of phagocytic capacity and expression of many other accessory molecules that interact with receptors on T cells to enhance adhesion and signalling (co-stimulation); for example, LFA-3/CD58, ICAM-1/CD54, B7-1/CD80, B7-2/CD86 and CD83.69,70 (see Table 2 and 3) Expression of one or both of the costimulatory molecules B7-1 (CD80) and B7-2 (CD86) on the DCs are essential for the effective activation of T lymphocytes, and, for IL-2 production.71 These co-stimulatory molecules bind the CD28 molecules on T lymphocytes. If this fails to occur at the time of Ag recognition by the TCR, an alternative T lymphocyte function may result, namely induction of anergy.54, 71 Another CD80/86 ligand, CTLA-4, is also induced on activated T lymphocytes, and this may contribute a negative regulatory signal.72, 73

Dendritic cells are a major source of many cytokines, namely, interferon-alpha (IFN-a), IL-1, IL-6, IL-7, IL-12 and IL-15 and also produce macrophage inflammatory protein (MIP1g), all of which are important in the elicitation of a primary immune response.74-80 Also, there is evidence that the cytokine secretion pattern of the plastic-adherent monocyte-derived DCs (grown in GM-CSF and IL-4) can be induced along the Th1 (IL-12) or Th 2 (IL-10) cytokine secretory pathway. Interleukin-12 production is critical for the promotion of an effective cellular immune response by activating and differentiating T lymphocyte to the Th 1 pathway. Its secretion appears to be inhibited by various tumour-derived substances, including nitric oxide (NO), prostaglandin E2 (PGE2), IL-10, IFN-a itself, the p40 homodimer of IL-12, and transforming growth factor b (TGF-b), which is regarded predominantly as an immunosuppressive cytokine.74, 78-80

Dendritic cells, grown and matured in vitro, can synthesize IL-10 in a continuous manner. Zhou and Tedder (1995) have found IL-10 transcripts, in CD83+ cells isolated from peripheral blood by RT-PCR analysis, and de Saints-Vis et al. (1998) have observed IL-10 synthesis by CD14+ DCs of myeloid origin. 74, 81 It is well established that monocytes and macrophages synthesize IL-10.82 It is also well known that IL-10 has an important regulatory role on monocyte function and on DC maturation.83-85 Furthermore, IL-10 has been documented to have a significant inhibitory effect on several aspects of APC function, for example, the expression of co-stimulatory molecules and the ability to synthesize IL-12.83, 85, 86 Importantly, IL-10 treated-DCs can be tolerogenic.87-90 Dendritic cells secreting IL-10 exhibit minimal or no stimulatory properties in primary MLRs and are markedly inhibitory to T cell proliferation induced by polyclonal activators91 Thus, IL-10 producing DCs are functionally and phenotypically inhibitory accessory cells and putatively tolerogenic.92

Figure 1: Morphological characteristic of human immature DC from peripheral blood after immuno-magnetic bead isolation (Wright-Giemsa, x 600)

Figure 2: Morphological characteristic of human mature and activated DC from lymph node after immuno-magnetic bead isolation (Wright-Giemsa, x 600)

DC DEATH (APOPTOSIS)

Although previous studies have demonstrated that developmentally and functionally end-stage DCs undergo apoptotic cell death, the possibility that apoptosis contributes to the regulation of the DC pathway at others stages of DC development has not been extensively explored.93

Functionally distinct apoptotic schedules were associated with different phases of DC development when multipotent CD34+ progenitor cells were treated with GM-CSF, TNF ± SCF (c-kit ligand).94 During early phases of growth (days 0-3), unselected progenitors underwent apoptosis. During intermediate stages (days 3-7), high levels of apoptosis resulted in the preferential selection of DC precursors, as revealed by the substantial expansion of DR+ CD33+ CD13+ cells. Late apoptosis (after day 10) was associated with the death of mature DCs. Apoptotic events surrounding the earlier periods were related to the exogenous addition of TNF-a and appeared to be mediated by fas. In contrast, those events associated with terminally differentiated DCs were fas-independent, because there was no correlation between fas expression and cell death. Recent studies by Canque et al (1998) have shown that the inclusion of TNF-a during DC development produces apoptotic events that selectively promote the CD1a-dependent DC pathway from GM-CSF, TNF-a treated CD34+ cord blood progenitors cells, lending support to the above observations.95 The susceptibility to apoptosis was remarkedly decreased when DC precursors were treated with GM-CSF or IL-3, further supporting that these cytokines are viability (anti-death) factors for DCs.95

A number of researchers have concentrated on TRANCE or RANK-1, a TNF member identified by several groups recently. It increases the viability of mature myeloid DCs; both mouse DCs generated from the marrow or human DCs developed from monocytes.96, 97 TRANCE does not alter adhesion and co-stimulatory molecules like ICAM and B7, but it does make the mature DCs stay alive longer and express several cytokines genes, including IL-1, IL-6, IL-12 and IL-15. These responses are important features of mature DCs, which are sometimes referred to as activated and superactivated. When the mature DCs encounters the correct TNF family member, its viability is improved and cytokine production is enhanced, thus, creating a longer lasting and more effective Ag presenting cell.96, 97

These studies show that, at least within the myeloid lineage, the activation of distinct apoptotic processes regulates DC development and homeostasis. Although suppression of apoptosis may prolong the survival of mature DCs, activation of apoptosis is required for the selective expansion of multipotent DC progenitors. These data also provide insight into the mechanisms of myeloid lineage selection by cytokines such as TNF-a, which may promote both cell death and survival.

DENDRITIC CELL DISTRIBUTION

Dendritic cells in peripheral blood

Although human PBDCs were first isolated in 1982 their phenotype has been poorly defined due to their low numbers and the lack of specific markers by which they could be clearly identified. Hitherto, purification of PBDCs has relied upon either sequential depletion of other PBMC subsets or on their physical properties, such as their capacity for transient adherence to plastic and their low density, thereby, permitting separation over density gradients.98 Using such techniques, it has been demonstrated that the most potent allostimulatory fraction of PBMCs possessed a phenotype characterized by high levels of HLA class II expression and absence of markers for other cell lineages.99 These studies and new techniques, such as immuno-magnetic bead depletion and fluorescence flow cytometry, have enabled the further characterization of PBDCs and the demonstration of at least two subpopulations of cells.100-102

Using three-colour flow cytometry, two subpopulations of HLA-DR+ PBDCs, characterized by the phenotypes CD2-CD13- CD33dim CD11c- HLA-DR+ and CD2+ CD13+ CD33bright CD11c+ HLA-DR+ respectively, have been documented.100, 101, 103 The morphology of these two subtypes differ, the CD11c- population possess a lymphoid appearance and the CD11c+ population possess a monocytoid morphology.101, 103 Further, both subsets lack expression of the LC marker CD1a and express only low levels of adhesion and co-stimulation molecules CD80, CD86 and CD40, suggesting that these cells are relatively immature.100, 101, 103 However, when cultured, both populations develop into cells with typical DC morphology that express high levels of adhesion and co-stimulatory molecules and possess potent allostimulatory function.100,101 The CD33dim subset possess a lower allostimulatory activity which increases in culture along with expression of both HLA-DR and CD33.100 However, it has recently been demonstrated that although both subsets are stimulatory in the MLR only the CD2+ subset is capable of presenting Ag to naïve CD4+ T cells suggesting that these subsets of DCs may be functionally distinct.104

In order to facilitate the study of PBDCs, two markers specific for these cells have been identified in recent years. CD83 is a 45 kd member of the immunoglobulin superfamily that is virtually specific for DCs derived from the peripheral blood.49,105 Although CD83 was not originally found on freshly isolated DCs but only after in vitro culture,49 a later report identified a small subset of DCs that expressed CD83, when freshly isolated, and a larger subset that upregulated CD83 expression upon culture.102 The 55 kd actin bundling protein (p55) is a highly conserved protein important in the rearrangement of the cytoskeleton, cell motility and phagocytosis. Monoclonal antibodies against p55 detect this protein in 96% of PBDCs but not in other PBMC populations and, therefore, may be useful in the quantification and purification of PBDCs.50

While DC subsets have been defined in the peripheral blood their characterization has remained inconsistent reflecting, in part, the different purification protocols and MAbs used to define each subset. It remains to be established if one subset of PBDCs is the precursor for the other or whether each subset has developed along a distinct maturational/functional pathway. It has also been suggested that one subset may be more mature by virtue of being tissue-derived and migrating to lymph nodes or spleen whilst the less mature is directly derived from the bone marrow.101

Dendritic cells in peripheral tissues and lymph nodes

Dendritic cells have been identified within the interstitial space of most human tissues although notable exceptions are the absence of DCs in the cornea and central nervous system.106, 107 Within tissues, DCs exist as trace populations and may be identified by the combination of DC morphology and immunohistochemical labeling to demonstrate the expression of high levels of HLA-DR, CD1a (on LCs in the epidermis) and S100, and the absence of other lineage markers.108, 109 There is evidence that tissue DCs are derived from circulating blood precursors which bind to the endothelial receptors ICAM-1, V-CAM-1 and E-selectin through the expression of CD11a/CD18 and CD49d and cutaneous lymphocyte antigen (CLA), respectively.110, 111 This recruitment of DCs to tissue may be partly mediated by the local production of cytokines such as GM-CSF and by systemic signals such as bacterial lipopolysaccharide (LPS).112, 113 Within tissues, DCs reside in an intermediate stage of maturity as cells specialized for Ag uptake and processing. Tissue DCs take up Ag both in the fluid phase by macropinocytosis and via receptor-mediated endocytosis using the mannose receptor to ingest glycosylated Ag, and via the FcgRII (CD32) cell surface receptors take up antibody-bound Ag.114 Endocytosed particulate matter is channeled via an acidic vacuolar route to the intracellular class II compartment where antigenic peptides are assembled onto MHC class II molecules for presentation to T cells.114 The functional status of the DCs is regulated by a variety of cytokines and upon exposure to TNF-a, IL-1 and bacterial LPS, DCs undergo further maturation and migration.115-117 This involves downregulation of Ag uptake and processing, increased expression of the co-stimulatory molecules CD40, CD54, CD80 and CD86, enhanced Ag presenting function30, 118 and migration from the tissues to the lymph nodes and spleen.119-121 These changes in DC maturity and function, following exposure to cytokines and products of bacterial and cellular degradation, conform to the ‘danger’ hypothesis for activation of the immune response, as proposed by Marzinger (1994).122

DCs migrate to the secondary lymphoid tissues via the afferent lymphatics as veiled cells, so called because of their characteristic sheet-like lamellipodia. Cannulation of dermal afferent lymphatic vessels in human subjects has demonstrated an increase in CD1a+ DCs leaving the skin following exposure to contact sensitizers.123 There is also evidence from animal transplantation models that solid tissue DCs may migrate via the blood to the spleen.121 The mechanisms of homing to the LNs and spleen are not fully understood but recent evidence suggests that expression of certain isoforms of the hyaluronic acid receptor (CD44) may be important.124 In LNs, DCs reside within the T cell paracortical regions as interdigitating DCs (IDCs), whilst in the spleen they are located in the marginal zones at the periphery of the periarterial sheaths.106 The IDCs nonspecifically cluster T cells through their expression of adhesion molecules and present Ag in association with class II molecules. Antigen-specific T cells may then proliferate provided those co-stimulatory signals are communicated via CD40, CD80 and CD86 to their ligands on T cells. Production of cytokines such as IL-12 by the DCs further directs the evolving immune response along a Th1 pathway.75 It is apparent that the responding lymphocytes signal back to the DCs via MHC-TCR and CD40-CD40L interactions to promote further upregulation of DC co-stimulatory function.76 In addition to the IDCs of the T cell regions, DCs that are distinct from follicular DCs have recently been described in the B cell germinal centre.77 This suggests that they may play a role in T-dependent B cell memory immune responses. Kinetic studies in mice demonstrate a rapid DC turnover and life cycle in LNs, with DCs undergoing apoptosis after presentation of Ags to T cells.106, 125

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Copyright date: 10 January 2001

Correspondence: Professor O.Eremin, Section of Surgery, E Floor, West Block, Queen's Medical Center, University of Nottingham NG7 2UH

The Royal College of Surgeons of Edinburgh

invites applications for
THE KING JAMES IV PROFESSORSHIPS

Up to five lectureships will be awarded annually by the College in open competition to distinguished practitioners of surgery or dental surgery - two to dental and three to surgical Fellows of the College. The courtesy title of Professor will be accorded to the individuals for the duration of the College year in which their lectures are delivered.

For further information, contact:

The Awards and Grants Secretary The Royal College of Surgeons of Edinburgh Nicolson Street Edinburgh EH8 9DW

Tel.: +44 (0) 131 527 1618; Fax: +44 (0) 131 527 1730; Email: e.wright@rcsed.ac.uk

Closing date for applications is: Friday 7 September 2001

©2001 The Royal College of Surgeons of Edinburgh, J.R.Coll.Surg.Edinb.

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