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REVIEW ARTICLE
By
From the Haematology/Immunology/Transfusion Medicine Research Group, Christchurch School of Medicine/Christchurch Hospital, Christchurch, New Zealand.
The description of skin dendritic cells (DC) by Langerhans in 1868 was followed by prolonged speculation as to their function. Steinman and Cohn identified mouse spleen DC in 19731 and initiated a series of experiments that established lymphoid tissue-derived DC as potent stimulators of primary immune responses.2-5 The observation that similar cells were present in the nonlymphoid tissues of both rodents6-8 and humans,9,10 combined with early evidence that they played an important role in heart and kidney transplant rejection,11-14 generated further interest in DC. However, a paucity of markers for DC, the difficulty distinguishing DC from monocytes/macrophages (Mo/MØ), and the problems involved in purifying DC made for slow progress. Nonetheless, several laboratories persisted with their investigations, leading to the current acceptance that DC represent discrete leukocyte population(s) of specialist or "professional" antigen presenting cells (APC), with an extraordinary capacity for initiating primary (and secondary) T-lymphocyte responses.15,16
It is now possible to grow DC-like cells in culture17-21 and the first monoclonal antibodies (MoAbs)22,23 that react with human DC are available. DC migration24 is probably directed by a range of mediators and recent data suggest that reciprocal T-lymphocyte feedback provides antigen (Ag)-specific control of DC Ag presentation.16,25,26 This new understanding of DC function may provide opportunities for therapeutic intervention in bone marrow transplantation (BMT), solid organ transplantation, and autoimmune disease. Protocols for clinical immunotherapy programs, targeted on malignant cell Ag or infectious agents, are being designed to exploit DC as "nature's adjuvant" for optimal therapeutic vaccination.
A practical issue facing hematologists is the lack of a clear definition of a DC. This, combined with uncertainty as to the ontogeny of DC, limited data as to the interrelationship of different DC populations, and the fact that activation/differentiation events may dramatically change the morphology, molecular expression (phenotype), and function of DC, has created difficulties. This review will concentrate mainly on the myeloid lineage-derived DC, which associate with T lymphocytes within lymphoid tissue, to provide critical APC activity for initiating specific T-lymphocyte activation and proliferation.15,27,28 Follicular dendritic cells (FDC), which are present within the B-lymphoid follicle, do not originate from the BM, have a different phenotype, and retain Ag for prolonged periods, thereby restimulating B lymphocytes and perhaps T lymphocytes, will not be reviewed. Nor will dendritic epithelial cells, a specialized subset of T lymphocytes with extensive membrane processes, which are found in epithelial surfaces in mice but are rare in humans. Myeloid DC should be further distinguished from thymic DC, which appear to derive from a lymphoid stem cell.29 Thymic DC (and perhaps other lymphoid lineage-derived DC) have an entirely different role30,31; they delete maturing T lymphocytes and the prediction that they may have different properties from the myeloid-derived DC, although controversial, has received experimental support.32
The cardinal properties of the myeloid lineage-derived DC (hereafter DC) include (1) the ability to take up, process, and present Ag; (2) the ability to migrate selectively through tissues; and (3) the ability to interact with, stimulate, and direct T-lymphocyte responses. DC may be the only cell capable of stimulating a naive T lymphocyte but other "nonprofessional" APC (and DC) can stimulate experienced (activated or memory) T lymphocytes. As such, DC have unique cell interaction capabilities, some of which relate to their extensive cell membrane processes that are acquired late during DC differentiation/activation (Fig 1). DC have been defined, as of necessity, by these specialized functional characteristics15,27,33 to distinguish them from Mo and MØ.
The Existence of a Lineage?
Functional Activity of DC
Isolation of DC A comprehensive review of methodology27 is available. DC purifications generally use one of two main approaches.
Cytochemical Characteristics
Problems Defining the DC Lineage There are notable species differences. In mice and rats, BM and blood DC precursors express few MHC Ags and are poor stimulators in the allo-MLR.20,82,83 However, in humans, BM is allostimulatory44,84 and at least one or more fresh DC populations in blood are potent allostimulatory cells.52,57,85 Other surface molecules on DC have different patterns of expression between the species, eg, CD11c86 and CD187 (see Cell Surface and Other DC-Associated Molecules).A Working Definition of DC The putative DC lineage encompasses DC populations with very different properties, characteristic of their differentiation/activation state. Although DC were named because of their distinctive morphology,1,7 this feature is insufficient to define a DC. A definition of a DC must emphasize its ability to migrate and to stimulate a primary T-lymphocyte response. A consensus working definition might be:
DC express a repertoire of molecules common to other leukocytes, eg, MHC molecules, CD45 (leukocyte common) isoforms, adhesion molecules etc. These have dominated attempts to produce DC lineage specific MoAbs but persistence has resulted in some useful new reagents (Table 1).
Relatively DC-Specific Ags The difficulties in isolating pure DC for immunization and screening of MoAb undoubtedly limited endeavors and hence the reagents available. It seems unlikely that DC lack unique membrane features and cell-surface molecules. Indeed, when sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) protein analysis of pure human tonsil DC proteins was compared with other leukocytes,91 DC appeared to have a very different protein composition, even if this level of resolution did not identify DC-specific molecules.Mouse DC The 33D1 rat MoAb92 identifies a low-density Ag on mouse (marginal zone) spleen DC. The antibody does not stain DC in cryostat sections and does not react with LC. No biochemical data on the Ag are available. Nonetheless, this antibody has proved extremely useful for C lysis of mouse spleen DC.
Other Animal Species Another potential member of the integrin family that is preferentially expressed on rat DC is defined by the MoAb MRC OX62.96 The Ag is found on other cells but has considerable potential for defining DC.49Humans The CD1 gene family includes at least three relatively well-characterized gene products: CD1a, CD1b, and CD1c, which have similarity with MHC class I molecules and are expressed by cortical thymocytes. LC express CD1a and variable amounts of CD1c87,97 while CD1b has been reported on dermal and migrating LC.98
Non-Lineage-Restricted Membrane Ags on DC Broadly Expressed Molecules DC express the CD45 Ag60 including the CD45RA, CD45RO, and CD45RC isoforms.51,78,112,113 The CD45RO is probably induced by activation.105 Signaling via the phosphatase active CD45 cytoplasmic portion may contribute to DC function.60Myeloid Ags In humans, most blood DC express CD33, an early marker of myeloid differentiation.44,80 LC and dermal DC express some CD33.116,117 Expression of CD33 appears to be reduced on tonsil DC,46,118 suggesting that it downregulates as DC differentiate. CD33 has been postulated to be a sialoadhesin119 but its function on DC is unknown.
Lymphoid Ags Freshly isolated human blood DC probably express low levels of CD278,130 as do rat DC. However, cultured human blood DC,70,130 LC,117 and tonsil DC131 lack CD2 Ag. The CD5 Ag is found on blood DC.78,85,120 The CD4 Ag was identified on tonsil DC,46 LC,97 and recently on blood DC.105,120,132 Lymphoid-derived mouse DC express CD8.133Adhesion Molecules Clearly, DC are involved in a number of adhesive interactions during their migration and subsequent interaction with T lymphocytes. The initial tethering and rolling of DC precursors on endothelium may prove to be mediated by selectins. Firmer DC adhesion and migration through vessel walls is likely to involve integrins and intercellular adhesion molecules (ICAMs) or other Ig superfamily members. Integrins, the CD44 Ag or the syndecans may mediate interstitial tissue interactions. The more stable DC interactions with epithelia probably involve the cadherins.
Potential Ag Uptake (C, Fc, pattern recognition) Receptors Intact pathogens or antigenic components must bind to DC via opsonization (C and antibody) or other nonspecific recognition receptors.
Costimulatory/Signaling Molecules (see DC Functional Properties section for functional data) The CD40 molecule was first identified on human tonsil DC46 and then LC39 after activation in vitro. Blood DC express low levels of CD40 and upregulate its expression in vitro and after cytokine exposure.26Activation Markers Several inducible (activation) surface Ags are found on DC. CD25 (IL-2R39,81 ) is induced on DC (cytokine receptors are discussed in Molecular Events Involved in DC Clustering and Signaling to T Lymphocytes section). Other markers, eg, CD98 (4F2)113 and CMRF-37178 are found on DC. The Reed Sternberg/Hodgkin cell (RSC/HC) associated CD30 Ag179 has not proved inducible on DC in limited studies to date. CD38 is expressed on tonsil DC (in preparation).Inhibitory Molecules Migrating LC undergo apoptosis in vitro.180 DC have also been shown to undergo steroid and UV light-induced apoptosis.181 They are predicted to express the Fas Ag (CD95)16,182 but confirmation of a functional effect on DC is awaited. Human DC express Fas-ligand. A subset of mouse CD8+ spleen DC express Fas-ligand.183Cytoplasmic Molecules The hamster MoAb M342 stains an intracellular granule-associated Ag within mouse IDC and some B lymphocytes.47 Absent from freshly isolated spleen DC, the Ag is induced by culturing. Another MoAb, MIDC-8, stains similarly, but this Ag is not present in B lymphocytes.47Transcription Factors It is logical that certain transcription factors (or combinations) will be associated selectively with the DC lineage. The early data reinforce the concept that DC form a unique lineage, with distinct transcriptional control of several genes.
Novel DC Molecules The search for novel molecules that play a role in the special functions of DC as an APC continues apace using both MoAbs and the new differential display technology. Several novel molecules expressed relatively selectively in DC have been identified, and further information on these will soon be available.
Immunophenotypic and functional analyses have defined the different DC populations (Fig 3). The interrelationship of nonlymphoid and lymphoid tissue DC has been inferred from the behavior of murine LC both in vitro and in vivo, the homing of DC injected into recipients and Ag tracking studies. The ability of DC to migrate into the tissues and from there to the LN is critical to their overall function as APC.
Bone Marrow BM isolated from mice20 and rats83 does not have constitutive allostimulatory activity. Mouse BM cultured in low21 or high concentrations82 of GM-CSF, with further mechanical (decanting) selection against granulocytic development, enables a DC-like population to emerge. Curiously, these cell preparations lacked significant expression of the mouse DC markers, NLDC-145 and N418,20 but were allostimulatory and homed to LN. Subsequent reports by others describe the generation of DC from mouse BM using GM-CSF and interleukin-4 (IL-4).202,203 OP/OP M-CSF-deficient mice204 have deficiencies in MØ populations but have been reported to have normal LC and DC networks,205 although LC were said to be reduced by 40% in number and abnormal in morphology.206
Blood DC Mouse peripheral blood mononuclear cells generate DC-like cells when cultured in GM-CSF alone,19 suggesting a circulating DC precursor. These are destined to provide interstitial DC in nonlymphoid tissues, including the skin and liver.49Nonlymphoid Tissue-Derived Interstitial DC There is an extensive network of interstitial DC encompassing virtually all organs except the brain, parts of the eye, and the testes.7,10,37,226 These cells develop from precursors in the blood7 and provide a sentinel system of APC. LPS,115 GM-CSF,227 IL-6, and probably other stimuli recruit precursors to the tissues. Mo-DC migrate in response to classical chemoattractants (formyl peptides and C5a) and some chemokines (MCP-3, MIP-1 , and RANTES) but not IL-8.228 A basal rate of tissue entry is boosted (5- to 10-fold) by tissue damage/inflammation, ie, "danger" signals.229 The kinetics of the DC response in the lung are rapid, similar to the neutrophil response. Freshly recruited mouse LC and other interstitial DC are N418-, NLDC-145- but become NLDC-145 + in time and may express low levels of the macrophage-associated F4/80 Ag.
LC Epidermal LC form an extensive suprabasal network with branched cytoplasmic processes extended in physical contact with multiple adjacent LC.33 CD1a+ LC containing Birbeck granules are found in the dermis97 and may represent cells moving into the afferent lymphatic system. The number of LC ( 1,000/mm2 ) vary according to site.232 LC in the skin are subject to neuroendocrine control and are intimately associated with nerve endings. A low level of in vivo LC proliferation (? recently entered blood precursors) has been described.233 A population of CD1a- dermal DC (immunohistology97 ) or CD1adim (immunofluorescence/isolated cells) is also present.74 Factor XIIIa positive dermal DC may be another potential subset110 among a substantial dermal MØ population.104
Interstitial DC First noted as strongly MHC class II positive cells with irregular membrane processes in rat tissue sections,6-8,37 these DC are distinguished from MØ by phenotype and radiosensitivity.239 Similar DC have been observed in mouse heart and kidney,43 although the level of MHC class II expression in the mouse appears reduced, hindering detection. In humans, DC have been documented in most organs, including liver,185 kidney,9 heart, and other connective tissue and tend to be associated with vascular structures.10
Mucosal Surface-Associated DC An interdigitating sentinel epithelial network of DC has been described in the mucosa of the oral cavity, intestinal tract, and the respiratory tract, of mice, rat, and humans.243-246 These mucosal DC mature after weaning and their phenotype is responsive to external environmental influences.247 Inflammatory stimuli also recruit DC to the mucous membranes.248 Mucosal DC are also likely to have properties peculiar to the epithelial (external environment) surface that they serve.Afferent Lymphatic DC (veiled cells) Various stimuli, including contact sensitizing agents, micro-organisms, and inflammatory mediators stimulate migration of DC from the skin, other nonlymphoid interstitial sites, and the mucosal surfaces into afferent lymph, where they are recognized as veiled cells.64,252-254 The agents, which mediate these effects, have all proved to be relatively nonspecific, eg, LPS, IL-1, and TNF- .230,255 Thus, the activation of DC and the subsequent trafficking appears to be initiated by the Ag independent "danger signals."229 Active changes in DC, dependent on tyrosine kinase activity, are involved in DC emigrating from tissues.171 Large mononuclear cells with veiled morphology were first isolated from pig45 and human256 lymph and constituted up to 20% of lymph cells. Peripheral DC migrate toward afferent lymphatics and traffic in the draining lymph to the LN where, after entering via the cortical sinus, the DC migrate to the T-lymphocyte-rich paracortical areas.257 This changes the DC homing characteristcs such that mouse spleen DC are unable to enter skin or heart transplants.258
Skin-Derived Lymphatic DC Microscopic studies on skin have identified LC migrating from the epidermis into dermal lymphatic channels.231 Veiled cells have been identified in skin lymphatics.256,259 In addition to their dramatic morphological appearances some cells remain CD1a+259 or, in the mouse, retain the NLDC-145 marker. Some appear to retain Birbeck granules.260 LC induced to migrate on contact with Ag present the Ag as the draining lymphatic DC.65,261 LC migrate out of mouse skin grafts forming cords of exiting NLDC-145+ cells in the lymphatics231 and migrate from human skin fragments placed in vitro.98,137 LC when reinfused home to the skin.Nonlymphoid Organ DC Visceral organs are presumed to respond to similar stimuli with an efflux of interstitial DC into draining lymphatics. The close association of DC with vascular structures make this likely and migration from rat liver to coeliac nodes has now been observed. Tissue DC migrate out of transplanted heart and kidneys into the circulation and the spleen.262 In rats peritoneal inflammation induces DC traffic into lymphatics.Mucosal Surface-Derived Lymphatic DC Similar cells are found in the afferent lymph from rat gut.164,263 Increased numbers of these cells are obtained by removing mesenteric LN and direct thoracic duct cannulation. They are also mobilized by LPS.264 The ultimate fate of these cells in the intact host is not yet clear.Lymph Node and Tonsil DC Practical issues have dictated that, apart from immunohistological studies in humans, functional data on LN-derived DC have been confined virtually entirely to other animals. Once again, it is prudent to consider LN draining skin, visceral organs, and mucosal (gut and respiratory) tissues as somewhat different. It has been assumed (there have been few direct comparisons) that the DC isolated from intact lymphoid tissue2 represent the IDC observed by light and electron microscopy266 and immunophenotyping.267Splenic DC Given the spleen's different functions and dependence on a blood and not a lymphatic supply for cellular entry and exit, it seemed likely that splenic DC populations might have different characteristics.16 At least two subpopulations of DC have been defined in mouse spleen.47 The first, situated in the T-lymphocyte area in a periarteriolar distribution (ie white pulp), does not express the DC marker 33D1 or HSA but are NLDC-145+/DEC-205+ and can be induced to express M342 by culture.47 This population equates to the IDC described above. Direct visualization identifies a second population of DC in mouse spleen at the peripheries of the white pulp the marginal zone. These cells have the inverse phenotype, ie, they are 33D1+ HSA+ NLDC-145- M342-.47 LPS appears to induce the marginal zone DC to mature and migrate into and then out of the T-lymphocyte area.272 These marginal zone, 33D1, and HSA-positive DC may represent a circulating blood-derived DC more equivalent to human blood DC and comparative studies with other forms of lymphoid tissue-derived DC are merited. Indeed, GM-CSF generates DC from mouse splenocytes that resemble LC in phenotype and function.273 In contrast, different techniques isolate a (? lymphoid-derived) CD8+ DC subset from mouse spleen with different properties183 their anatomical location is yet to be established.
Gross phagocytic and proteolytic activity are more features of professional scavengers such as MØ.15 In contrast, relatively limited phagocytic/pinocytic capabilities provide DC with enough Ag to be processed into peptide for T-lymphocyte activation. After Ag uptake DC migrate, meet, and initiate membrane interactions with T lymphocytes and costimulate specific T-lymphocyte responses. Stimulation of T-Lymphocyte Responses Alloantigen DC are considerably more effective than purified blood B lymphocytes and Mo, as stimulators in an allo-MLR.46,57,58 Tonsil B lymphocytes are often poor stimulators of an MLR.46 On the other hand, activated B (memory) lymphocytes, either LPS stimulated or EBV-derived human B-lymphoid lines, have significant allo-MLR activity55,56,143,281 and likewise, cytokine-activated and differentiated Mo and endothelial cells may acquire greater MLR activity. Indirect responder APC contributions are minimal.57 The allogeneic MHC- peptide complex may involve self-antigens, including processed self MHC molecules or acquired exogenous or endogenous56 viral Ags. Extensive DC differentiation and activation may occur during the time course of an MLR and it does not measure Ag uptake and processing.Autologous Ag Purified mature DC stimulate significant autologous T-lymphocyte proliferative responses the autologous MLR.46,52,60,61 These "background" results have been downplayed but may be significant, eg, in peptide-based cancer immunotherapy (see later). It is assumed that the preparation of DC leads to activation and expression of endogenous autoantigens or exogenous Ags. Some reduction in autologous MLR occurs when foreign Ags are removed from preparative media. In mice, increased specific responses upon rechallenge with BSA support the notion that fetal calf serum is a significant sensitizing Ag.
Exogenous Ags Purified Ags have been used to prime mouse DC to generate primary immune responses. In vivo administration of splenic DC after in vitro incubation with ovalbumin,62 sperm whale myoglobin,63 or hen egg lysozyme63,67 have been shown to stimulate strong Ag-specific responses when T lymphocytes from these mice are rechallenged with Ag in vitro. Similar results with fluoroscein isothiocynate65 and other Ags282,283 have been obtained using mouse LC. Pulsing DC with PPD or an immunodominant 19-kD protein derived from M tuberculosis primes for strong specific proliferative responses in vivo.284,285 A variety of tumor-derived peptide Ags have been used to prime DC in vivo (see DC Vaccination and Immunotherapy) for T-lymphocyte helper and cytotoxic responses. In vitro priming has also been studied, mainly in mouse models, and primary in vitro responses using peptide pulsed DC have been reported.286Other Systems DC are accessory cells for CD3 mitogenesis a paradoxical and variable result, which presumably reflects either contaminating FcR-positive cells or validates reports of the expression of CD64 and CD32 on less differentiated DC. DC also stimulate in oxidative mitogenesis assays for APC function.71,73,269
Inhibition of T-Lymphocyte Responses There are at least three different scenarios in which DC may mediate alternative APC functions by deleting inhibiting or anergizing T lymphocytes.Thymic DC The majority of thymic DC are located at the cortico-medullary junction.30,300,301 Extensive mouse studies using congenic strains, transgenic animals, and artificial thymus cultures have established that a high proportion of early thymocytes receive a negative, apoptotic signal if the evolving T-lymphocyte TCR binds with high affinity to "self antigenic peptide plus MHC" on APC within the thymus.302,303 Thymic DC, which were until recently presumed to be of myeloid origin, are thought to be the APC responsible for the induction of tolerance. It is suggested that low concentrations of Ags from nonthymic sources are available to thymic DC to ensure systemic tolerance but there are problems with this concept.229 The outcome of thymic DC Ag presentation was thought to depend on the stage of T-lymphocyte differentiation (mature or immature) and not any intrinsic property of thymic DC. Both isolated splenic and thymic DC can initiate primary in vitro responses when they are cocultured with mature T lymphocytes. Conversely, splenic DC can induce T-lymphocyte tolerance after introduction into thymic lobes.31Lymphoid Precursor-Derived DC Shortman et al have promoted the alternative concept that thymic DC are derived from a common lymphoid committed progenitor. The progenitors seed the thymus coincidentally in proportion with thymocyte progenitors29 and the resulting CD8+ thymic DC deliver tolerogenic signals.32,133,304 Mouse thymic DC appear to deliver a FasL dependent negative signal to CD4+ T lymphocytes183 and an alternative inhibitory signal to CD8+ T lymphocytes.32 Similar CD8+ DC have been isolated from peripheral lymphoid tissues, including mouse spleen.133 These DC, described as a subpopulation in lymphoid tissue preparations, may play a role in maintaining peripheral tolerance.Peripheral DC Lacking a Costimulator Phenotype The postulated differentiation and activation of myeloid DC into fully competent potent APC is a regulated event16 and there is considerable control of the expression of several crucial DC costimulator molecules.25,26 In a normal inflammatory/immune response, DC are thought to upregulate these molecules (Fig 4, top). However, DC costimulator activity is likely to remain low in the absence of inflammation229 and these cells may migrate into LN. As a result DC could tolerize or anergize T lymphocytes they encounter in the peripheries.16 Furthermore, DC may downregulate costimulator activity in certain circumstances, thereby rendering them ineffective as APC. Neonatal respiratory tract DC are also hyporesponsive.247 Further evidence that myeloid DC may be tolerogenic comes from recent data suggesting DC targeted with the 33D1 antibody induced specific T- and B-lymphocyte tolerance to rat IgG2b antibody.307 Immature DC, which lack costimulator molecules, may tolerize allograft recipients.308,309
Terminally Differentiated DC Few DC are found in the efferent lymph. It is probable that central migration of Ag loaded DC and subsequent T-lymphocyte activation triggers DC terminal differentiation resulting in DC death.16 No direct observational data of DC death within LN has been reported but in vitro analysis suggests that DC are susceptible to apoptotic signals,181 after induction of Fas or alternative death signaling molecules. It is feasible that DC, which have interacted productively with T lymphocytes, receive late negative signals which render them ineffective APC.16 This would reduce multiple Ag processing and the possibility of inappropriate autoreactive APC function.DC Depletion Studies No natural model of DC deficiency exists. Immunodeficient nude mice15 and rats7 have normal or increased numbers of DC. Likewise, RAG1/RAG2 deficient mice, which lack T- and B-lymphoid cells, have normal DC numbers, including thymic DC.
The ability of DC to take up Ag and process it is highly dependent on the stage of DC differentiation. In vivo this relates to DC location. In vitro it relates to the time in culture, degree of activation, and antigen/T-lymphocyte exposure. Antigenic Material MØ may be more effective than DC as scavengers as a result of their portfolio of different nonspecific Ag (scavenger) receptors.150 In early studies, intravenous (IV) administered material such as colloidal carbon, peroxidase, and other Ags were found predominantly in MØ, although lesser quantities were noted in nonlymphoid tissue DC.2,7 Immunogenic fragments of foreign proteins are found in mouse spleen DC after IV administration.312 Phagocytosis of whole cells by DC in vivo has been reported,313 and DC draining the gut appear to contain phagocytic remnants.81,164 Liver DC precursors have phagocytic capability and migrate quickly (retaining immature cytological appearances) into the afferent lymph where they are no longer phagocytic.49 Several different investigators have now documented that administration of sensitizing Ag to the skin surface can be traced to LC and then to afferent lymph and IDC.65,312 Intradermal or mucosal administration of Ag primes afferent lymph DC in mice,67,314 rats,245,263 sheep,252 and humans50 to stimulate T-lymphocyte responses.Ag Uptake Preliminary data suggest DC use a variety of membrane receptors for taking up Ag. The resulting receptor-antigen complexes may traffic between cell types321 and perhaps even from MØ to DC. "Cross-priming," ie, Ag transfer from one cell to APC, may complicate interpretation of in vivo experiments.FcR The FcR repertoire on DC was described in the Potential Ag Uptake (C, Fc, Pattern Recognition) Receptors section. Specific antibody presumably acting via these receptors facilitates APC function of sheep lymphatic DC.252,322 Antibodies that bind to isolated LC are internalized.323 Fanger et al155 have used bispecific antibodies to confirm that CD64 and CD32 stimulate human blood DC to phagocytose ox red blood cells but at less than half the rate of Mo. A secondary tetanus toxoid T-cell line response was increased when specific antibody was added to Mo-DC and Ag.149 Culture of blood DC and LC downregulates their FcR and this presumably prevents further Fc Ag loading.C Receptors The trace levels of receptors were described in the Potential Ag Uptake (C, Fc, pattern Recognition) Receptors section. C components on the surface of organisms act as opsonins for the uptake of material in LC.33 C5a receptor (CD88) on DC have not been tested for Ag uptake.154 No data on the function of CR3 or indeed CR1 and CR2 on fresh blood DC are available but these receptors downregulate upon culture and activation of LC.324Pattern Recognition Receptors Bacteria express a large number of complex CHO molecules on their surface which may bind to pattern recognition receptors,150 many of which have a lectin-like specificity. Mannose containing residues bind to a mannose receptor protein present in high density on MØ,95,160 but there are subtleties as to the exact sugar specificities of binding, indicating several receptors may be involved.325 Related mannose binding proteins circulate in plasma.168 The mannose receptor binds bacteria and stimulates phagocytosis by MØ.160 Studies on mouse DC suggest mannose-like receptors are present317 and recent experiments in humans show that rapid uptake of mannose-conjugated BSA by GM-CSF/IL-4-differentiated Mo-DC is inhibited by mannose.162MHC and Other Membrane Cycled Molecules Cycling of surface MHC class I molecules (the class I groove is closed) as an Ag uptake mechanism is thought to be very limited, although some peptide exchange may happen at the surface. The CD1 molecule may be associated with Ag uptake, particularly nonprotein Ag.320,323,327,328Ag Processing Endogenous Ag is degraded by intracellular proteases and peptidases to provide peptides in the cytosol. These peptides, bind to transporter (TAP) gene products and are delivered to the MHC class I compartment to be incorporated in the nascent peptide binding groove generated by folding of the class I molecule before moving to the cell surface. This does not occur in the presence of proteasome or Golgi transport inhibitors and defines a conventional pathway. In DC, several additional mechanisms also operate allowing exogenous Ags to be presented on MHC class I molecules.332 Firstly, it is now clear that DC take up Ags by macropinocytosis and release Ag into the cytosol for classical TAP-dependent MHC class I presentation.333 Secondly, peptides produced in high concentration externally may exchange with peptides on mature MHC class I molecules. A third mechanism may involve carrier molecules or chaperones such as hsp96, capturing peptides and delivering then via the DC surface to the endoplasmic reticulum, where they are released, processed, and incorporated into MHC class I molecules.
MHC-Peptide Presentation DC actively synthesize MHC class I molecules and mature DC show high-density surface expression.15 Again, MHC class II molecule synthesis is active in fresh blood DC35 and LC62 and surface MHC Ag expression increases markedly on culture, eg, LC in GM-CSF.38,343 It is noteworthy that low-dose GM-CSF decreases synthesis of class I in mouse MØ.21 IL-4 also upregulates MHC class II production125 as of course does IFN- . Isolated mouse liver DC are MHC class II- and require interaction with collagen to induce its expression.173 After in vitro culture DC synthesis of MHC Ags is reduced,344 however, cultured LC can passively acquire Ag fragments that do not need processing.234 Indicative of their specialized function, DC retain class II antigenic peptide complexes for prolonged periods (1 to 2 days) in culture,62 whereas MØ have a turnover measured in hours.345 The biochemical explanation for a lesser glycosylation of DC MHC molecules346 and any functional consequence remain elusive.
The formation of DC-T lymphocyte clusters in vitro only occurs after multiple transient DC-T lymphocyte interactions.60,275,350 It is an active process and may start in the afferent lymph.187 Cluster formation requires an intact DC cytoskeleton and protein kinase C activation350 to initiate adhesion interactions.60 This is initially an Ag-independent process275 but, once cognate-specific T-lymphocyte recognition occurs, additional events stabilize the cluster (Fig 4).
Adherence The DC-T-lymphocyte interaction is stabilized by adhesion molecules.59,70,134,135,269 ICAM-3, which is constitutively expressed on DC in high concentrations, provides the predominant initial adhesion interaction with LFA-1 on T lymphocytes.135 ICAM-2 on DC does not appear to contribute much to this particular adherence interaction.136 ICAM-1 is expressed in relatively lesser amounts on resting DC but is induced rapidly on DC as a result of retrograde signaling from the T lymphocyte,135 thereby stabilizing the cluster.Costimulator Molecules The term "costimulation" is used to describe the additional signals required to initiate T-lymphocyte activation apart from an adhesion interaction.351 Without "costimulation," specific Ag triggering of T lymphocytes may lead to anergy or cell death.351-354CD80 (B7.1) and CD86 (B7.2) An excellent review in Blood describes the properties of these two members of the Ig superfamily.354 They bind different sites on the CD28 molecule (present on 80% of human T lymphocytes), thereby delivering a significant cyclosporin A-independent costimulatory signal. A second CD80/86 ligand, CTLA-4, is expressed on activated T lymphocytes and provides an alternative negative signal.355 Differential T-lymphocyte responses are attributed to CD80 stimulation (TH1 ) or to CD86 stimulation (TH 2 ) in vitro and in vivo.356
CD40 The CD40 molecule is a member of the TNF receptor (TNF-R) family. Its ligand CD40L, a TNF- -like molecule, is expressed on T lymphocytes within a few hours of their activation.365 The CD40L on T lymphocytes provides an essential costimulatory signal for CD40+ B lymphocytes. The CD40 molecule was described on human tonsil DC,46 and subsequently noted to be present in low density on resting human blood DC26,51 and LC.39 It is rapidly upregulated after a brief period of tissue culture. In humans the cytokines IL-1, IL-3, GM-CSF, and TNF- increase CD40 expression, whereas IL-2, IL-4, IL-6, IL-12, and IFN- 26 do not. CD40 is upregulated on CD34+-generated DC.366 An analysis of human CD40:CD40L interactions suggests two functions for the CD40 molecule on DC.26 Firstly, retrograde signaling via CD40 was the most potent stimulus identified to date for upregulating CD80/CD86. Secondly, despite this effect, soluble CD40L and CD40-Ig inhibit DC stimulation of allogeneic T lymphocytes,26 suggesting that the DC CD40-CD40L T-lymphocyte interaction provided an additional costimulatory signal. Significant additional inhibitory activity occurred when both CTLA-4Ig (blocking CD80/CD86) and CD40-Ig were used to block a DC stimulated MLR.
HSA/CD24 An MoAb able to block costimulator function was shown to recognize HSA367 and costimulatory activity was attributed to HSA on mouse LC.172 Mouse HSA transfectants stimulated T lymphocytes and double-transfection studies inferred HSA and CD80 had synergistic costimulatory activity.368 The human homologue CD24 is not present on DC, and similar experiments produced no evidence to support the view that human CD24 has costimulator function.369OX40L OX40, another member of the TNF-R family,370,371 is present on activated peripheral CD4+ and a subset of activated CD8+ T lymphocytes. The OX40L is found on EBV-transformed B lymphocytes372 and CD40L-stimulated B lymphocytes.373 It costimulates OKT3, phytohemagglutinin (PHA), or phorbol 12-myristate 13-acetate (PMA) activated T lymphocytes372 and it seems likely that the OX40L:OX40 binding contributes to DC:T-lymphocyte interactions.4-1BBL 4-1BB is expressed on activated thymocytes and T lymphocytes.374-376 PHA activation of T lymphocytes induces 4-1BB within a few hours.377 The 4-1BBL has been identified on LPS-activated BM MØ and on anti-Ig activated B lymphocytes.375,378 Transfectants expressing 4-1BBL costimulate CD3 triggered T lymphocytes and mimic the effect of antibody crosslinking 4-1BB on T lymphocytes.376,379 4-1BBL is inducible on B-cell lymphomas and acts as an effective costimulatory molecule.380 Again, it seems likely that DC express 4-1BBL, if not 4-1BB, as well.CD6 Ligand Crosslinking studies suggests that CD6 can function as an accessory protein in T-lymphocyte activation.381,382 A ligand for CD6, ALCAM (activated leukocyte adhesion molecule), has been identified.382 ALCAM has 5 Ig-like external domains and mediates cell adhesion to CD6. It is not yet known whether this ligand pairing provides a costimulatory interaction. However, as ALCAM is induced on activated Mo, whether it is expressed or not on DC is a relevant question, particularly as CD6 antibodies can influence the autologous MLR.383,384SLAM Ligand A novel 70-kD glycoprotein designated SLAM (CDw150) has recently been described as yet another member of the Ig superfamily, which has limited similarity with CD48 and LFA-3.385 SLAM is constitutively expressed on peripheral blood, memory T lymphocytes, and induced on naive T lymphocytes after activation. It has recently been identified on blood DC and upregulates with activation.113 Monovalent antibody bound to SLAM enhanced Ag-specific T-lymphocyte proliferation and cytokine production.MHC Signals Complete or partial activation of the responding T lymphocyte has the potential to provide molecular feedback by T-lymphocyte membrane molecules or secreted products, ie, cytokines (Fig 4). The DC MHC/peptide:TCR/CD4 or CD8 T-lymphocyte interaction has been suggested to provide a retrograde signal to DC after cognate recognition of Ag by the TCR.16 Data have accumulated to suggest the cytoplasmic portion of MHC molecules, notably class II, mediate intracellular signaling events in other cells281,386 and preliminary data suggest that class II signaling upregulates CD80/CD86 on Mo. The effect of crosslinking MHC class II molecules on DC costimulator molecule expression is under investigation.Cytokines and Chemokines The issue as to which of the many immunologically important cytokines (reviewed elsewhere) are expressed by DC remains a somewhat vexed one. Conflicting data have arisen because the purity of some DC preparations may have allowed significant cytokine release from contaminating populations. Even more relevant, different states of differentiation/activation, particularly DC phagocytosis/pinocytosis, may profoundly influence DC cytokine production.IL-1
TNF- secretion by mouse DC has not been studied in detail, although human studies suggest there are low levels of TNF- mRNA in blood389,392 and tonsil DC.16 No biologically detectable TNF- 392 was secreted, but this may vary with the stimuli used. DC-like cells generated from CD34+ cells produce TNF- when stimulated via CD40.366 TNF- antiserum inhibited a DC stimulated allo-MLR,392,393 but this neutralized the TNF- produced by activated T lymphocytes, which acts as a significant autocrine factor.392 Lymphotoxin (TNF- ) has limited expression in DC at the mRNA level389 but the significance of this is unclear.
GM-CSF Small amounts of GM-CSF mRNA have been reported in human blood16,389 and tonsil16 DC, but evidence that this results in secretion of active GM-CSF is awaited.IL-6 Mouse LC produce IL-6394 and DC are thought to be the major source of IL-6 in the mouse LN. Northern blot analysis failed to detect IL-6 mRNA388 but RT-PCR detects small amounts in human blood DC16,389 and larger amounts in tonsil DC.16 Although IL-6 protein was not obviously produced by blood DC,388 viral exposure induces IL-6 secretion.395 High numbers of DC used as APC are associated with IL-6 production and allogeneic cytotoxic T-lymphocyte responses are blocked by IL-6 antibody.396IL-7 IL-7 is a pleiotropic cytokine397 that has an important role in the differentiation of B lymphocytes, the maturation of thymocytes,398,399 and as a growth factor for mature T lymphocytes.400,401 Highly purified CD4+ as well as CD8+ T lymphocytes proliferate in response to IL-7 and a comitogen.402 The expression of IL-7 in human CD83+ blood DC was reported to be variable at the mRNA level.389 Sorg et al403 have shown that activated CMRF-44+ DC but not freshly isolated DC express IL-7 mRNA. Moreover, purified CD14+ Mo failed to express IL-7. An IL-7-neutralizing MoAb was shown to inhibit DC stimulation of an allo-MLR.IL-10 Intriguing RT-PCR data suggest that DC may produce IL-10, which may further regulate T-lymphocyte responses.389IL-12 IL-12 consists of two chains, a p40 protein and a p35 protein, which are both required for activity. Mouse DC coordinate secretion of the p40 and p35 components (p40 alone may inhibit) to produce functional IL-12339,404 and IL-12 production by human DC has also been described.405 Microparticle adsorbed versus soluble Ag may activate IL-12 mRNA synthesis.315 At least in vitro, the production of IL-12 by DC may drive the bias toward a TH1 response so often observed experimentally. Intriguing data suggest that human TH2 clones can induce DC IL-12 and that their cytokine profile was influenced by the APC.406IL-15 IL-15 has no homology with IL-2, but the two cytokines share a number of biological activities, presumably as a result of their shared receptor chain.407 IL-15 is produced by several cell types, whereas IL-2 is derived primarily from T lymphocytes. This, and the wide distribution of the IL-15R chain, suggests IL-15 has a different physiological role to IL-2. IL-15 is produced by Mo, MØ,408 and Mo-DC. Blood-derived DC have been shown to induce IL-15 in RNA and protein.409
IFN No IFN- or - is produced by unstimulated DC,16,389 whereas Mo produce large amounts of both. HIV-1132 and HSV395 infection induced high levels of DC IFN- production.
Other Cytokines No biologically active IL-2 is produced by DC.16 Low-level IL-3 transcripts have been found by some investigators389 and not others (unpublished). Neither IL-4 nor IL-5 mRNA was detected by RT-PCR in CD83+ cells, a feature which distinguishes DC from Mo.389 Equivocal IL-11 mRNA levels were reported in CD83 + blood DC.389 IL-13 was not found by RT-PCR.389
Chemokines DC may well produce several of these low molecular weight compounds, which facilitate the migration of leukocytes. MIP1 and MIP1 mRNA have been reported in CD83+ blood DC.389 Their production by LC has been reported391 and MIP1 is produced by CD34+-generated DC.366 At least some mRNA for RANTES and MCP-1 may also be present in blood DC.389
Cytokine Receptors DC growth, differentiation, migration, and functional Ag processing and presentation are all regulated by cytokines. The expression of cytokine receptors on DC is likely to determine many of these events16,410 and again the data suggest their density varies according to the state of DC differentiation/activation.411IL-1R The type I and the type II IL-1R both bind IL-1 and as well as the IL-1R antagonist, but the two receptors use different signal transduction pathways. Direct binding of IL-1 to mouse LC (~500 sites/cell) with nearly an order of magnitude less binding to spleen DC has been shown.410 Purified human blood and tonsil DC express mRNA for type I but not type II IL-1R.16 Direct labeling of IL-1R with Cdw121 and MoAb has recently confirmed their expression on human LC.411 IL-1 and Il-1 induce CD40 on human blood DC.26
TNFR The type I TNFR (55 kD) and the type II TNFR (75 kD) differ in their intracellular portions, suggesting different signaling pathways. Studies on human blood DC have confirmed mRNA and surface expression of both types.392 Ryffel et al412 demonstrated type II TNFR on thymic DC using histological techniques.
GM-CSF Receptor (GM-CSFR) The presence of GM-CSFR on DC was anticipated given the effects of this cytokine on DC phenotype, migration and growth (In Vitro Cultivation of DC and DC Lines).17,38 Mouse DC have been shown to have GM-CSFR by direct binding studies (~3,000 sites/cell)410 and RT-PCR analysis has shown GM-CSFR mRNA in human blood and tonsil DC.16 Direct staining of blood DC with CDw116 MoAb also identified GM-CSFR.389 The majority of LC express the GM-CSFR chain but only 15% of CD1a cells expressed the GM-CSFR chain, although the latter upregulated in culture.411
IL-2R The IL-2R (CD25) was not detected on human tonsil DC46 but has been detected on blood DC,51 although the IL-2R chain was not detected.389 Again these differences may reflect the stage of cell differentiation. IL-2R were induced by culture of murine LC414 and by GM-CSF on rat lymphatic DC.81 IL-2R was induced on cultured DC by CD40L.366 Despite these findings no functional effects of IL-2 on DC have yet been described.
TGF-R Endoglin (CD105) is present on DC389 and activated Mo and acts to bind TGF 1 and TGF 3 .151 These cytokines may well help direct DC motility.151
Other Cytokine Receptors DC do not express the M-CSFR410,413 or respond to M-CSF or G-CSF,413 although a neonatal-skin-derived LC line may do so.415 An RT-PCR analysis found no evidence of IL-4R on human DC,389 which is surprising given the effects of IL-4 on DC precursor growth and differentiation. IL-6R and gp130 were detected on a subset of human LC.411 IFNR have been described on a subset of LC.411 A number of studies suggest DC respond to IFN- by inducing MHC class II Ags, ICAM-1,416 CMRF-44,22 CD80, and CD86.26
Chemokine Receptors The C-C chemokines MCP-3, MIP1 , and RANTES elicit chemotactic migration and an increase in intracellular Ca2+ in DC.228 DC did not respond to C-X-C chemokines IL-8, IP-10, or the C-C chemokines MCP-1 and MCP-2.228
T-Lymphocyte Responses The circumstantial evidence suggests DC are capable of costimulating a wide range of T-lymphocyte responses. Antigen type, route of administration, the overall cytokine milieu, and the genetic background (this has a profound influence on TH1 v TH2 responses) will influence that response.
Production of DC in vitro has provided cells for basic scientific studies and for therapy. The divergent approaches adopted for growing DC and the problems inherent in identifying DC require some scientific caution. Normal DC and DC-Like Cells Several cellular sources have been used to generate DC.BM GM-CSF-generated mouse BM cells resemble DC morphologically and have most but not all the phenotypic characteristics of DC.20,21,284 The ability of these cells when injected in vivo to migrate and function as DC is most encouraging.82 Several groups have added IL-4 to GM-CSF in order to produce mouse DC,202,203,425-428 but this may enhance the nonspecific stimulation of T lymphocytes.425 In vitro flt-3 ligand contributes to mouse lymphoid (and it is anticipated myeloid) DC production.304
Cord Blood CD34+-Selected Blood Progenitors Caux et al101 described the culture of CD34+ cord blood cells in GM-CSF and TNF- to produce a population of CD1a cells (5% to 15% of the progeny) with marked allostimulatory activity. Yields were approximately 107 CD1a cells from 106 CD34+ cells at 2 weeks. Santiago-Schwarz et al429 have described similar results. It appears that IL-3 can substitute for GM-CSF in this system.163 A further report366 explored the use of additional CD40L stimulation and provided a more detailed phenotype, indicating some heterogeneity in the resulting cell population. This complex cell population, which includes DC, can process soluble Ag and prime naive T lymphocytes.430 Other groups have followed suit using similar or modified conditions.218,431-433 The inclusion of SCF for the first 5 days increased cell yields approximately fivefold (day 12 yields were approximately 10-fold starting CD34+ cells).433 The resulting populations were heterogenous but late addition of IL-4 (day 12) induced CD1a expression and increased the allostimulatory activity of the cells. Strobl et al434 used SCF, GM-CSF, TNF- , and TGF 1 to generate CD1a+ progeny from CD34+ cord blood cells and showed that TGF 1 would substitute for serum in this system.
Mobilized Peripheral Blood CD34+ Progenitors Mobilized CD34+ cells have been used as another source of progenitors for attempts to grow DC. Bernhard et al431 used GM-CSF to culture CD34+ progenitors producing 30% to 60% CD1a+ cells within a 20- to 40-fold expanded total cell population at day 15. Mackensen et al432 added GM-CSF and IL-4 to a cocktail of SCF, EPO, IL-1 , IL-3, and IL-6, thereby generating a high proportion (45%) of CD1a+ cells. Siena et al218 used SCF and flt-3 ligand to supplement GM-CSF and TNF- culture of CD34+ mobilized cells. Yields were of a similar order (4 × 107 cells from 106 CD34 cells) with 33% to 55% CD1a+ cells in the progeny. A recent study210 raised the possibility that CD34+ cells showed commitment to epithelial-based CD1a+ or CD1a- nonepithelial DC populations: expression of the skin homing receptor defined a CD1a+ CLA+ LC precursor.
Blood DC and Their Precursors Markowicz and Engleman17 established that human blood DC (and their precursors) obtained by Percoll gradient separation and phenotypic selection could be maintained in GM-CSF for 4 to 6 weeks. The cells formed clumps in fluid phase culture and after several days developed allostimulatory cells with a DC morphology.PBMC (blood Mo) Sallusto and Lanzavecchia149 cultured adherent human PBMC in GM-CSF and IL-4 or GM-CSF and TNF- and found potent APC populations emerged. Elegant studies established that the GM-CSF and IL-4-generated APC could process and present soluble Ag to tetanus toxoid-specific clones. Conversely, GM-CSF- and TNF- -generated APC were less effective at processing specific Ag but had equivalent allostimulatory capacity. Romani et al435 also used GM-CSF and IL-4 to generate DC-like progeny from adherent PBMC. The resulting cells contained a significant proportion of DC-like cells (3 to 8 × 106 cells from 40 mL blood at 5 to 7 days). The experiments did not clarify from which component of PBMC the APC were derived.
LC and Tissue DC The technical requirements for their preparation and the low yield make it unlikely that epidermal LC will be a future source of DC for therapy. Although dermal DC migrate readily from skin explants, this source is unlikely for practical reasons.DC-Derived (transformed) Cell Lines The availability of well-characterized DC lines is essential to enhance progress.Transformation of Normal DC Some putative mouse DC lines have been described,439,440 but their DC origin has not been widely accepted, nor has further data with these accrued. Significant progress has been made since using retroviral transformation of murine DC preparations. O'Neill and Ni441 transformed mouse spleen cells and obtained cell lines, which had several characteristics of DC. Transformation of murine progenitor MØ and LC has generated cell lines with antigen-presenting characteristics of DC.442 Superinfection of GM-CSF-transduced mouse BM cells with c-myc and c-raf oncogenes produced 33D1 and DEC-205+ DC clones, which have been cultured for 6 months.443DC Malignancies It would be most curious if DC did not undergo spontaneous malignant change.
The difficulty in identifying DC has been limiting but the CD83, CMRF-44, and CMRF-56 reagents to track DC have encouraged new clinical studies. Infectious Disease HIV Patients infected with HIV lose the ability to mount primary immune responses and this may, in part, be due to reduced DC function.457,458 MØ secondary antigen presenting function is unaffected in HIV+ subjects. An original report documenting HIV within LC by in situ hybridization has been confirmed by observing direct LC infection using MØ-trophic HIV strains.459 Approximately 1% of LC in acquired immunodeficiency syndrome (AIDS) patients are likely to be infected.460
Other Clinical Viral Infections There is good evidence that viral Ags for influenza276 and Herpes simplex286 are presented by DC to generate T-lymphocyte responses.Mycobacterial Infection Human DC present mycobacterial Ags for primary T-lymphocyte responses.77,292-295 Mycobacteria have been located within the cutaneous infiltrates of leprosy patients466 and DC constitute a minor population of the inflammatory infiltrate.Other Bacteria, Protozoal, and Fungal Infections Clearly DC present a range of Ags from different organisms, eg, Chlamydia296 Leishmania,48,317,318 Candida52 in vitro to T lymphocytes and for in vivo responses. Although major changes in DC numbers, localization, and function might be expected in these infections, the inability to monitor DC readily has prevented further clinical observations. However, a recent study467 showed that dermal DC but not LC engulf Borrelia burgdorferi (Bb), the organism associated with Lyme disease, and present Bb Ags.Immunodeficiency There have been several reports of deficient APC function in primary immunodeficiencies, including hyper IgM syndrome.468 No DC specific defect has emerged as yet but deficiencies in MHC class II Ag expression and CD40L expression (hyper IgM syndrome) are likely to profoundly affect DC function.Autoimmune Disease It is no surprise that DC are also the most efficient APC for endogenous self Ags.338 Certainly, DC are capable of generating strong autologous responses in vitro this is generally assumed to reflect exogenous Ags but may reflect activation of truly autoreactive clones the specificities of those autoreactive clones have not been tested. Known autoantigens, eg, myelin basic protein or thyroid extract, may be incubated with DC and these will initiate autoimmune disease in mice.469 Experimental models of diabetes in mice suggest that APC may trigger autoimmunity by initiating a local or systemic response to an infective agent.470 Enhanced cluster formation by DC from nonobese diabetic (NOD) mice has been reported471 and DC incriminated in the islet pathology, which evolves in BB rats.472 In contrast, transfer of DC from pancreatic LN but not DC from other sources inhibited the development of autoimmune disease in NOD mice,473 perhaps by reinforcing tolerance.
Allergy and Hypersensitivity LC are intimately involved in contact allergen sensitization261 and appear to have an affinity for certain metals and haptens. Some blood DC and LC express IgE receptors (see Cell Surface and Other DC-Associated Molecules) and may be capable of initiating the late phases of type I hypersensitivity. They may also be involved in the immunological hyper-reactivity of psoriasis364,484 and atopic dermatitis.466 DC appear in the early stages of the inflammatory infiltrate and appear to be located in dermal clusters in psoriasis but appear in diffuse infiltrates in atopic dermatitis.466DC in Malignancy The biology of DC in malignant disease is currently arousing great interest. Animal data from Muller et al486 suggests that skin carcinogenesis is associated with a paucity of DC. There is a large body of literature alluding to the effects of UV radiation on murine DC.487 This appears to reduce DC antigen-presenting function, probably via a direct effect on protein synthesis. DC are associated with tumors in mice; however, further mouse data have called into question whether DC recruited into skin tumors indicate a host immune response to tumor.488
DC may sensitize for allogeneic responses either (1) directly, by presenting preformed MHC ± minor Ags, or (2) indirectly by processing and presenting MHC alloantigens presumably as peptides.14 UV irradiation of blood products abrogates MHC allosensitization, presumably through an effect on DC.505 Cyclosporin A may affect DC activity506 and unstimulated interstitial DC are steroid sensitive.14 Solid-Organ Transplantation Soon after interstitial DC were identified it was suggested that these might be the passenger leukocytes which contributed to the strong primary allograft reaction.6,9,11,12 Formal proof that DC in heart and kidney allografts contributed to the immunogenicity of a graft was then obtained.13,14 Treatment of mouse pancreatic islet507 and thyroid508 grafts with antibodies binding DC and C before transplantation prolonged their survival. Despite other expectations, allografted thymic DC appear to be immunogenic in mice.509 The situation with liver allografts in these models is less clear, because this organ appears to have special properties.173 Depletion of donor kidney DC in clinical practice appears to have some clinically beneficial effect510 but maximum efficacy will require very effective DC depletion.Blood and BM Transplantation There is little direct experimental data. CD34+ cells stimulate an allo-MLR84 and human BM contains DC-like cells.44 Therefore, direct priming by graft APC of residual host T-lymphocyte immune response, which survives the myeloablative/immunosuppressive conditioning before stem cell transplantation, may contribute to stem cell graft failure/rejection. Fractionation of CD34+ cells to avoid allostimulatory activity, while retaining stem cell reconstituting activity (CD34+ HLA-DR-), might be considered to avoid this.
Clinical hematologists cannot fail to be intrigued by current investigations using DC as cellular therapy. As "nature's adjuvant," DC may be the ideal vehicle for immunization against infectious agents, malignant tissue, and even autoreactive lymphocytes. Investigators are constructing cellular/molecular vaccines, expressing GM-CSF, costimulator molecules, and TAA for tumor therapy. Some of these approaches, eg, GM-CSF, may recruit DC into tumors517 and others, eg, naked DNA vaccination, may be ways of delivering Ag into host DC.518 Well-defined autologous, Ag-loaded, DC preparations may prove to be the fastest and safest means of vaccinating patients. Clearly there is much to be learned: the type of DC preparation (particularly as lymphoid DC may tolerize) and how to expose them to Ag in vitro (or in vivo) requires considerable experimentation. It is salutary to realize the dramatic differences that DC activation/differentiation state, Ag preparation (protein or peptide) Ag modification, dose of DC and Ag, route of administration, host milieu, host genotype, etc may have on outcome. Furthermore, the possibility that myeloid DC may in certain circumstances suppress475,512,519 rather than enhance immune responses should be remembered. Infectious Agents DC have been used in vitro to present bacterial and viral Ags to T lymphocytes. Herpes simplex peptide derivatized with a triacyl tail and delivered to DC by liposomes was more effective than virus alone.286 Strong influenza virus-specific cytotoxic responses can be induced in vitro by using virus-infected DC,520 but depletion of Mo was necessary to remove an inhibitory effect. Peptide rather than whole virus may be better for DC-generated influenza responses.290 DC-generated responses to HIV proteins have been obtained in vitro.123,297,298,521Malignant Disease The immune response is capable of focusing on TAA which include (1) viral Ags in malignancies with a viral etiology; (2) tumor-specific Ags such as recombined or mutated oncoproteins and abnormally glycosylated molecules, or potentially (3) tumor-lineage-specific autoantigens. Responses may be directed against the malignant cells themselves or perhaps TAA presented by the stroma.Viral Ags Donor-derived cytotoxic T lymphocytes are active against post-BMT EBV+ lymphomas. Murine responses to HPPV have been produced in vitro and in vivo.Tumor-Specific Ags Some oncogenic proteins, which are unlikely to be subject to downregulation as a result of immuno-selective pressure, make ideal TAA. For example the bcr-abl fusion protein resulting from the 9; 22 translocation in CML and the PML-RAR fusion protein resulting from the 15; 17 translocation in promyelocytic leukemia, are potential leukemia-specific Ags. Likewise, mutations in oncogenes, eg, ras or tumor-suppressor genes, eg, p53 produce potential TAA, albeit with only 1 to 2 amino acid differences from the normal protein. The Ig idiotypes produced by non-Hodgkin lymphoma (NHL) cells are specific tumor markers, as are the Ig paraproteins produced in multiple myeloma. In some instances, the oncogenic changes may create a TAA on a malignant cell by indirect means. Thus, the mucin molecule, MUC-1, is abnormally glycosylated in breast, pancreatic, ovarian, and prostatic cancers as well as multiple myeloma, thereby exposing a repeated antigenic protein sequence.
Tissue-Specific Ags Several Ags are sufficiently tissue restricted to allow an autoimmune response to be efficacious, eg, MAGE, tyrosinase in melanomas, prostate-specific Ag, or prostate-specific membrane Ag (PSMA) in prostate cancer. The CD33 Ag might also be a sufficiently highly restricted myeloid lineage autoantigen for limited (possibly pretransplant) autoreactive therapy. Finally, overexpression of p53 wild-type protein in tumors may be another target autoantigen.DC Priming With TAA In Vitro Studies showed that both mouse spleen DC and LC could present tumor Ag and generate specific T-lymphocyte responses.522DC Vaccination With TAA In Vivo The T-lymphocyte responses described to date against known TAA and a host of as yet undefined TAA are often weak. Further, in any one individual with cancer, the host immune response to TAA has, by definition, failed. Therefore, reliable means of generating significant T-lymphocyte responses to TAA must be evolved, hence the interest in clinical DC immunotherapy. The data,190 suggesting that tumors circumvent DC in vivo, also argue in favor of this approach.
DC should now be recognized as unique subsets of leukocytes. Myeloid-derived DC have a unique ability to induce primary immune responses, but a lymphoid progenitor-derived DC with different properties has been described. It is unclear how much differentiation of Mo into DC occurs in vivo compared with the differentiation of Mo-DC induced by cytokines in vitro. DC show the essential properties required of APC: migration, Ag uptake, processing, and presentation of Ag and costimulation of lymphocytes. The MoAb, CD83, CMRF-44 and CMRF-56, are proving of value for studying human DC and a routine DC blood count based on CMRF-44 staining is now available (in preparation). The molecular events controlling DC function are not yet fully understood and their transcriptional control of critical genes will be an important new area. Surveillance DC respond to danger signals and initiate central migration and upregulation of Ag-presenting activity. The control of DC costimulation function is such that Ag-specific recognition and T-lymphocyte reciprocal signaling may render the DC Ag-presenting function effectively Ag specific. As such myeloid DC, as well as lymphoid DC, may contribute to central and peripheral tolerance. Better control of DC antigen-presenting function may improve BMT procedures and allow optimization of DC as "nature's adjuvant" for cancer immunotherapy.
Mouse BM-derived DC have been shown to phagocytose and process viable bacteria for presentation of both MHC class I and class II defined epitopes to T lymphocytes.538
Submitted October 2, 1996;
accepted June 6, 1997.
I am grateful to colleagues who contributed unpublished data to assist with writing this review. Dr G.J. Clark had major input into the preparation of the text and Dr D.B. Fearnley provided invaluable assistance. The constructive criticism of Dr M.A. Baird, Dr A. Heiser, Dr M. Kato, A.B. McLellan, Dr R.V. Sorg, Dr W.N. Patton, Dr A.B. Troy, and Dr S. Vuckovic was invaluable and greatly appreciated. S. Banks provided the considerable secretarial support required to prepare this review.
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