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Dendritic Cell Development: Multiple Pathways to Nature's Adjuvants

^a The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia;
^b Schering-Plough Laboratory for Immunological Research, Dardilly, France

Key Words. Antigen-presenting cells • Dendritic cells • Lymphoid-related dendritic cells • Myeloid-related dendritic cells • Langerhans' cells

Dr. Ken Shortman, The Walter and Eliza Hall Institute of Medical Research, Post Office, Royal Melbourne Hospital, Victoria 3050, Australia.

	Abstract

Top Abstract Introduction The Langerhans' Cell Model... Does the LC Model... Thymic DC The Development of Myeloid... Lymphoid-Related DC in Mice Lymphoid-Related DC in Humans Functional Differences Between... Conclusions References

 
Dendritic cells are a system of bone marrow-derived antigen-presenting cells specialized for interaction with T lymphocytes and essential for initiating primary T cell immune responses. Recent investigation indicates that dendritic cells are of diverse origin, with at least two types of myeloid precursors and a lymphoid precursor implicated in their generation. Mature dendritic cell subtypes, while sharing the capacity to activate T cells, show additional functional specialization. Some dendritic cells are equipped with additional mechanisms to regulate the response of the T cells they activate, while others are able to interact with B cells and modify B cell responses.

	Introduction

Top Abstract Introduction The Langerhans' Cell Model... Does the LC Model... Thymic DC The Development of Myeloid... Lymphoid-Related DC in Mice Lymphoid-Related DC in Humans Functional Differences Between... Conclusions References

 
In current immunological parlance, antigen-presenting cells are divided into the professional and the nonprofessional classes. The latter express major histocompatibility complex (MHC) molecules and can process antigens to produce the MHC-bound surface peptides recognized by specific T cell antigen receptors; however, they themselves lack the accessory molecules required to complete the process of T cell activation. The former, such as B cells and macrophages, not only process and present antigens but they also possess the additional accessory molecules required for T cell activation. In these terms dendritic cells (DC) must rank as the ultimate professionals.

DC are a widely distributed, trace population of bone marrow (BM)-derived leukocytes of unusual morphological form, originally described by Steinman and Cohn [1]. The primary function of DC is to capture and process antigens, then to present the antigenic peptides and activate specific T cells [2, 3]. They are even more efficient at this than B cells or macrophages and are probably the only cells capable of triggering a primary T cell response. DC have cytoplasmic extensions for maximizing T cell encounter, adhesion molecules to ensure intimate T cell contact, an efficient antigen-processing system and high surface levels of MHC molecules for peptide presentation, and costimulator molecules (including CD80-B7/1 and CD86-B7/2) to ensure T cell activation [2-8]. The signal exchange is two-way, with T cells inducing DC maturation and activation via CD40 ligand binding to CD40 [9, 10], and via cytokines such as GM-CSF.

Until recently it was a tedious process to obtain DC. They are sparsely distributed and are a minor component even of lymphoid tissues. The ability to produce DC in cytokine-driven cultures has made them more accessible and has encouraged attempts to use DC as natural "adjuvants" in tumor immunotherapy [11, 12]. There now appear to be several different routes by which the BM-derived cells that can be classed as DC may develop, and several different types of DC precursors. Although all DC present antigens and activate T cells, there is now evidence for specialization in function. Accordingly, in this review we will consider DC as a system of cells specialized for antigen presentation to T cells, rather than a unique cell type. We exclude from consideration follicular dendritic cells, the separate group of cells that localize and present unprocessed antigen-antibody complexes to B cells and promote B cell memory [13].

	The Langerhans' Cell Model of DC Life History

Top Abstract Introduction The Langerhans' Cell Model... Does the LC Model... Thymic DC The Development of Myeloid... Lymphoid-Related DC in Mice Lymphoid-Related DC in Humans Functional Differences Between... Conclusions References

 
The Langerhans' cells (LC) of the skin provide the clearest model of the life history of a DC [1, 14, 15]. There is a segregation of the antigen-uptake phase where LC serve as a sentinel at this potential site of antigen entry, of the migratory phase where LC move to the lymph nodes (LN) bearing processed antigen, and finally of the mature DC phase in the lymphoid tissue where interaction with specific T cells occurs. LC are BM-derived. The precursor which moves through the circulation and enters the epidermis has not been characterized, but culture studies indicate that it is a CD34⁺ cell bearing the skin homing cutaneous lymphocyte-associated antigen (CLA), and that it is already committed to LC development [16]. Since epidermal LC are present in Ikaros mutant mice, which lack all lymphoid cells [17], this precursor is likely to be of the myeloid lineage. LC express high levels of class II MHC, but differ from mature DC in expressing Fc receptors, expressing CD1a and in possessing Birbeck granules and the associated Lag antigen [18-20]. At this developmental stage epidermal LC differ functionally from mature forms of DC in being poor T cell activators but being capable of phagocytosis, receptor-mediated endocytosis and antigen-processing [21-23]. After a variable period of sentry duty in the skin, the LC may receive a "danger" signal [24] telling them to leave bearing samples of antigen from the local environment. This signal may be antigen uptake itself, or bacterial polysaccharide contact, or tissue damage, with tumor necrosis factor-alpha (TNF-) and interleukin 1 (IL-1) as likely final mediators [25-27]. The LC exit the tissue along specialized channels, move through the afferent lymph (as "veiled" cells) and finally enter draining LN to become mature DC. They have now lost much of their ability for antigen uptake but have acquired the capacity to present antigen and stimulate T cells. This coincides with a drop in FcRII, CD1a, Birbeck granules and an increase in class II MHC, B7/2 and CD40 expression. The exit of LC from the skin may be modeled in organ culture [28], the trauma of tissue isolation signaling the LC to leave and enter the medium. The maturation of LC to a mature DC may be induced in cell culture, the model system chosen to document most of the above maturation events [29-35]. GM-CSF has been shown to be the key cytokine for the final maturation process, with the other "myeloid hormones," macrophage colony-stimulating factor (M-CSF) and G-CSF, being ineffective.

	Does the LC Model Apply to All DC?

Top Abstract Introduction The Langerhans' Cell Model... Does the LC Model... Thymic DC The Development of Myeloid... Lymphoid-Related DC in Mice Lymphoid-Related DC in Humans Functional Differences Between... Conclusions References

 
This LC model is the current paradigm for DC function and life history. It is likely to apply, with local variations, to the DC found in other stratified epithelia, such as in the lung [36]. Known variations on the theme include a much higher rate of turnover in the lung and a mechanism to rapidly recruit DC into the tissue on antigen entry [37]. However, it is not clear that the LC model applies to DC found in other sites, such as tissue interstitial DC including skin dermal DC [38], or blood DC [39, 40]. Nor is it clear what proportion of DC found in the lymphoid tissues have arrived there bearing foreign antigens collected during a sentinel mode elsewhere, as opposed to DC arising directly from endogenous or blood-borne precursors, or derived from blood monocytes (discussed later). Such DC might only present antigens found in the local environment.

	Thymic DC

Top Abstract Introduction The Langerhans' Cell Model... Does the LC Model... Thymic DC The Development of Myeloid... Lymphoid-Related DC in Mice Lymphoid-Related DC in Humans Functional Differences Between... Conclusions References

 
One tissue where the LC model of DC development seems inappropriate is the thymus. The function of thymic DC is not to initiate a T cell response to foreign antigens, but rather to induce the death of any of the developing T cells which are potentially reactive with self-antigens [41, 42]. Recent studies by Brocker et al. [43] have confirmed that thymic DC mediate negative selection of T cells, rather than positive selection or immunity. Thymic DC turn over rapidly, as fast as the developing T cell population [44, 45]. An endogenous DC precursor, apparently identical with the early precursor of T cells, was identified in the adult mouse thymus by Ardavin et al. [46]. In transfer studies this endogenous precursor generated DC and T cells in the same ratio as found in the normal thymus, suggesting it was the major if not exclusive source of thymic DC [45]. Although this finding does not exclude the entry of some migratory DC from the bloodstream into the thymus, an endogenously generated DC population with a short life span seems more compatible with the requirements of thymic negative selection. Such DC would be more likely to present only locally synthesized self-antigens to T cells, rather than presenting foreign antigens collected in the periphery as in the LC model.

The level of locally derived DC in tissues other than the thymus is unclear, but the liver contains a DC-precursor population, and a self-tolerance and transplant-tolerance function for liver DC has been proposed [47, 48].

	The Development of Myeloid-Derived DC

Top Abstract Introduction The Langerhans' Cell Model... Does the LC Model... Thymic DC The Development of Myeloid... Lymphoid-Related DC in Mice Lymphoid-Related DC in Humans Functional Differences Between... Conclusions References

 
The concept that DC are of myeloid origin and are close relatives of macrophages received strong support once it was possible to generate DC in culture. Several lines of evidence now point to at least two pathways of myeloid DC development, leading to two closely related but differing types of DC. These lines of evidence from culture studies [15, 49, 50] are summarized below.

DC Development from Mouse BM and Blood Precursors
DC have been produced in culture from mouse BM or blood [51-55] and more recently from mouse liver [48]. The precursor cells were negative for class II MHC and nonadherent, but they have not been further characterized. Cell proliferation as well as differentiation occurred in these cultures. The product DC, which grew as characteristic clusters (similar to Fig. 1), expressed high levels of class II MHC, had dendritic morphology and were efficient stimulators of allogeneic T lymphocytes. GM-CSF, but not G-CSF or M-CSF, promoted this DC development, which was enhanced by the addition of TNF- late in culture. By performing such cultures in semisolid media, Inaba and colleagues produced colonies containing DC in association with macrophages and granulocytes [53]. This was the first clonal evidence for a common precursor for DC and the phagocytic myeloid cell types.

View larger version (101K): [in this window] [in a new window]   Figure 1. DC grown in culture from human CD34+ cord blood precursors. The cells were grown in GM-CSF and TNF- as described in [56, 60]. A) shows a typical DC cluster; B) shows individual DC.

Of all the cytokines tested in these CD34 precursor cultures, only GM-CSF and IL-3 had the capacity to support DC development in cooperation with TNF- (or TNF-ß) [62, 63]. However, both stem cell factor ([SCF]; c-kit ligand) and Flt3 ligand (Flt3L) were able to augment the DC yield if these key factors were present; SCF and Flt3L probably act by expanding the precursor cells, rather than inducing DC differentiation ([61]; unpublished data, C. Caux). Recently tumor growth factor-beta (TGF-ß) has been found to be essential for the development in culture of those human DC with the characteristics of LC, namely possession of Birbeck granules and expression of the Lag antigen [64]. In contrast, TGF-ß has been found to suppress production of the DC generated in cultures of mouse BM [55].

Two Pathways of DC Development from CD34⁺ Precursors
While after 12 days of culture of CD34⁺ cord blood precursors most product DC are CD14^– CD1a⁺, at early times (day 5-7) two subsets of intermediate DC precursors, identified by the mutually exclusive expression of CD1a and CD14, have been found to emerge independently [65]. Both these intermediate precursors mature by day 12-14 into cells with characteristic DC morphology, surface phenotype (CD1a⁺, high class II MHC, CD80, CD86, CD83, CD58), and function. However, the CD14^– CD1a⁺ precursors give rise to cells with LC characteristics (Birbeck granules, Lag antigen, E-cadherin), whereas the CD14⁺ CD1a^– precursors give rise to CD1a⁺ DC lacking Birbeck granules, Lag antigen or E-cadherin but expressing CD2, CD9, CD68 and the coagulation factor XIIIa found in dermal DC. Interestingly the CD14⁺ precursors, but not the CD1a⁺ precursors, are bipotent cells that can be induced, in response to M-CSF, to form macrophage-like cells lacking the ability to activate T cells. These two pathways of development have also been detected using peripheral blood CD34⁺ precursors separated on the basis of CLA expression [16]. Upon culture with GM-CSF and TNF-, the CLA⁺ progenitors differentiate into CD1a⁺, Birbeck granule⁺, Lag⁺ LC-like DC, while the CLA^– progenitors differentiate into CD1a⁺, Birbeck granule^–, Lag^– DC.

DC Development from Human Blood Monocytes
The concept that monocytes, as well as developing into macrophages, can also develop directly into DC was introduced over a decade ago but has been a subject of controversy. It is now accepted that blood monocytes can be induced to develop, without any proliferation, into a form of DC [15, 50]. Treatment with GM-CSF and IL-4 or IL-13 produces monocyte-derived DC with an immature DC phenotype (CD1a⁺, RelB expression, low expression of class II MHC in the intracytoplasmic compartment, low expression of CD80, CD86 and CD58, continued expression of the monocyte markers CD11b, CD36, CD68 and c-fms) [50, 66, 67]. These DC display efficient antigen uptake by macropinocytosis or receptor-mediated endocytosis through the mannose receptor, but have only a weak capacity to prime naive T cells. However, these immature DC undergo maturation when stimulated by the type of microenvironmental signals which induce DC migration in vivo (such as lipopolysaccharide, TNF-, IL-1) or by signals from T cells (such as CD40L) [67-69]. These monocyte-derived cells then acquire the characteristics of mature DC, including dendritic shape, loss of monocyte markers, loss of antigen uptake, upregulation of accessory molecules (CD80, CD86, CD58), translocation of class II MHC to the cell surface and finally a capacity to efficiently prime naive T cells. Akagawa et al. [67] have demonstrated that monocyte differentiation to macrophages (under the influence of M-CSF) or to DC (under the influence of GM-CSF) is initially reversible; however, DC development becomes irreversible under the influence of TNF-, as the M-CSF receptor c-fms is lost.

It is possible to integrate these lines of evidence from the culture studies on myeloid-derived DC. Based on the mouse DC cultures, after the multipotent hematopoietic stem cell there should be a myeloid progenitor cell common for granulocytes, macrophages and DC. These should further differentiate into the lineage-specific precursors revealed in the human DC cultures. These point to at least two types of myeloid-derived DC arising by two pathways from two separate precursors, as illustrated in Figure 2. Both types of product DC express the myeloid markers CD13 and CD33, but differ in other markers. The CD34⁺ CLA^– progenitors presumably produce the CD14⁺1a^– precursors, whereas the CD34⁺ CLA⁺ progenitors produce the CD14^–1a⁺ precursors. The CD14^–1a⁺ precursors then give rise to DC resembling epidermal LC. In contrast, the CD14⁺1a^– precursors represent bipotent cells that may be induced by M-CSF to form macrophages, but are induced by GM-CSF to form CD1a⁺ DC, resembling interstitial DC such as dermal DC. The monocyte-derived DC may be closest to the interstitial DC or CD14⁺-derived DC, in view of the lack of Birbeck granules in the progeny and the bipotent nature of the precursors. Indeed, it is tempting to speculate that interstitial DC may originate from monocytes that have entered tissues and encountered IL-4 or IL-13 released by tissue mast cells.

View larger version (27K): [in this window] [in a new window]   Figure 2. Development in culture of human myeloid-related DC. Several DC subsets may be produced by culture of CD34+ BM or cord blood populations. These originate from at least two different progenitors. The CD34+ CLA+ progenitors lead to CD1a+ precursors which further differentiate into LC-type DC. The CD34+ CLA– progenitors lead to CD14+ precursors which may differentiate either into macrophage-like cells (in the presence of M-CSF) or into DC resembling interstitial type DC (in the presence of GM-CSF). Blood monocytes may also develop much like the CD14+ intermediate precursors, and form either macrophages or interstitial-type DC. Fact.X111a: Factor X111a; BG: Birbeck granule; E-cad: E-cadherin; Lag: LC-associated granule.

	Lymphoid-Related DC in Mice

Top Abstract Introduction The Langerhans' Cell Model... Does the LC Model... Thymic DC The Development of Myeloid... Lymphoid-Related DC in Mice Lymphoid-Related DC in Humans Functional Differences Between... Conclusions References

View larger version (28K): [in this window] [in a new window]   Figure 3. Proposed lymphoid-related and myeloid-related DC development pathways. The diagram illustrates a diversity of possible pathways for DC formation. The three myeloid-derived pathways, one directly from blood monocytes without division, the other two by division and differentiation of a common myeloid precursor cell, all under the influence of GM-CSF, derive from the in vitro studies summarized in Figure 2, together with culture studies on murine DC. The lymphoid-related pathways, one entirely within the thymus, the other extrathymic and producing one population of DC found in spleen and lymph nodes, proceed without the myeloid hormone GM-CSF. Although the data at present support such a clear distinction between myeloid-derived and lymphoid-derived development, formal proof of the model at a clonal level has not yet been obtained.

The early thymic precursor population could be induced to form DC in culture, even from single precursor cells, with a cloning efficiency of around 70%; thus the majority of these cells isolated as T precursors were capable of forming DC [74]. However, since there is no corresponding clonal assay for T cell development and since 30% of the precursors die in culture, coincidence of T and DC precursors is not yet established. The development of DC in these cultures was rapid, with a fivefold expansion and near 100% purity in four days. The resultant DC had a surface phenotype characteristic of normal mouse DC (high levels of class II MHC, CD11c⁺, DEC-205⁺, CD80⁺, CD86⁺) and were efficient stimulators of naive allogeneic T cells in culture [74]. The main difference from the myeloid-derived DC cultures was the lack of any requirement for GM-CSF to stimulate proliferation or DC differentiation. The cytokine requirements for a maximal response were complex, including TNF- and IL-1, (both required from the initial stages of culture), IL-3, IL-7, SCF, Flt3L and CD40L. The lack of any requirement for GM-CSF did not appear to be a result of the added IL-3 providing alternative signals via the common ß-chain of the GM-CSF and IL-3 receptors, since DC were still generated in the absence of both cytokines [74]. One rationalization of the difference from the conventional cytokine requirements is that these DC represent a lymphoid-derived rather than a myeloid-derived lineage.

The Surface Phenotype and Development of Spleen and LN DC
The initial argument for a lymphoid-related DC in the peripheral lymphoid tissues of mice was based on surface phenotype. Around 50% of the DC in spleen express CD8 and DEC-205 and lack CD11b, and so resemble the apparently lymphoid-derived thymic DC [8, 70]. Artificial reconstitution of the DC of an irradiated spleen with the early thymic lymphoid precursor produced only CD8⁺ DC, whereas multipotent BM precursors produced both CD8^– and CD8⁺ DC [73]; this suggests that CD8 marks a lymphoid-related DC lineage and that the CD8^– DC represent myeloid-derived DC. However, other evidence indicates that CD8 is not invariably associated with lymphoid precursor-derived DC [74]. More secure markers of DC lineage origin are required to clarify the situation.

DC in Mice with Abnormal Levels of Cytokines or Cytokine Receptors
Manipulation of the levels of cytokines and cytokine receptors in mice has provided evidence for differences in DC origin and given support for the concept of lymphoid-related DC. Mice with the TGF-ß gene deleted lack LC, in agreement with the cell culture data, but have CD11c⁺ DC in their LN, suggesting not all LN DC are of LC origin [75]. Mice with the GM-CSF gene deleted, or the GM-CSF receptor common ß-chain deleted, still have a near normal complement of DC in their thymus and spleen, although there is some deficit in LN [76]. Conversely, mice with excessive GM-CSF, due to a transgene insertion, or subject to continuous injection of GM-CSF, show little increase in DC in thymus or spleen although they do show some increase in DC in LN and a massive increase in the peritoneal cavity [76, 77]. This suggests that the development of most DC in mouse thymus and spleen is GM-CSF independent, in agreement with the development in culture of DC from the thymic lymphoid precursor population. These results obtained by manipulating GM-CSF levels in vivo contrast with the massive increase in DC numbers occurring, with all subtypes of DC in all organs, when Flt3L is administered to mice [76, 77]. A high proportion of DC in mouse lymphoid organs are therefore GM-CSF and TGF-ß independent, but Flt3L responsive. This fits with the concept, but does not prove, that they are lymphoid-related DC.

DC in Mutant Mice Lacking Transcription Factors
Mice with the Rel-B gene disrupted display LC in the epidermis, but the DC of lymphoid organs are perturbed [78, 79]. The original results suggested a complete absence of DC in lymphoid organs, but more recent studies indicate that some DC are present, although abnormal in phenotype (Wu and Lo, unpublished data); the basis of the DC abnormality is not yet clear. Mice with the lymphoid-specific Ikaros transcription factor mutated possess myeloid cells and epidermal LC, but show severe disturbances in both lymphocyte and DC development. A dominant negative mutation of the DNA-binding domain of Ikaros leads to mice lacking all T cells, B cells, natural killer (NK) cells and their precursors, but possessing myeloid cells [17]. Wu et al. [80] have found that these mice have a near-complete lack of DC in their lymphoid organs, although they do have skin LC [17]. These developmental abnormalities were shown to be inherent to the mutant stem cells, rather than being a consequence of a disturbed environment. A different Ikaros null mutation of the C-terminus of the Ikaros gene gives a similar B and NK deficit but allows a delayed and restricted development of both T cells and CD8⁺ DC in the adult mouse [81]. These results present a powerful argument for a lymphoid-derived lineage of DC, but the DC deficit is so extensive as to suggest that the vast majority of murine DC are lymphoid-related. It seems more likely that Ikaros plays a role in the development of myeloid-derived DC, as well as of lymphoid-related DC.

	Lymphoid-Related DC in Humans

Top Abstract Introduction The Langerhans' Cell Model... Does the LC Model... Thymic DC The Development of Myeloid... Lymphoid-Related DC in Mice Lymphoid-Related DC in Humans Functional Differences Between... Conclusions References

 
The evidence for a lymphoid-related population of DC is less compelling in humans than in mice. Human DC, even from the thymus, do not express CD8, the marker that pointed to a lymphoid-related DC population in mice [82, 83]. Although many human DC express CD4, this provides little guidance to lineage origin since monocytes also express CD4. The markers found on most freshly isolated human DC resemble those seen on the apparently myeloid-derived DC grown in culture with GM-CSF and TNF-; conversely, growth in culture of human DC using the same cocktail of cytokines used to generate DC from the thymic lymphoid precursors in mice has so far failed to generate DC with any evident differences from those of the GM-CSF driven cultures (Caux and colleagues, unpublished data). However, one possible lymphoid-related DC lineage has recently been identified, following the isolation from tissue of the obscure, CD4⁺CD11b^– "plasmacytoid T cell" population; on incubation with IL-3, but not with GM-CSF, these cells developed both the morphological appearance and T cell stimulating activity of DC [84]. The cytokine requirements thus resemble those for the mouse putative lymphoid-derived DC, but at present there is no other evidence of lymphoid origin.

Despite the lack of a major group of human DC bearing markers of a lymphoid origin, a DC precursor population with lymphoid potential, similar to the murine early thymic precursor, has been isolated from human BM by Galy and colleagues [85]. This population produced T cells in a severe combined immunodeficiency syndrome-human mouse transfer system, and produced NK cells, B cells and DC, but not granulocytes or macrophages, in clonal culture systems. The DC formed did not display the extreme dendritic morphology of the human DC generated in standard GM-CSF stimulated cultures, but were within the range of forms seen with murine lymphoid-related DC. The normal progeny of these BM lymphoid/DC progenitors in vivo remains to be clarified.

	Functional Differences Between DC

Top Abstract Introduction The Langerhans' Cell Model... Does the LC Model... Thymic DC The Development of Myeloid... Lymphoid-Related DC in Mice Lymphoid-Related DC in Humans Functional Differences Between... Conclusions References

 
The foregoing evidence indicates that DC may be generated by different developmental pathways. Such DC may carry relics of their past lineage origin and this is probably the basis of some differences in antigenic markers. An essential question is whether these differences in origin in any way influence the final biological function. All DC have the capacity to present antigen and efficiently activate T cells; this has been the major criterion for classifying them as DC. However, there are now documented examples of differences in function between DC subtypes. These findings suggest that the DC sublineages are functionally specialized, although in most instances alternative interpretations are possible. These differences might also reflect specialized stages of development within one lineage, or simply be a consequence of the anatomical location or microenvironment of the individual DC.

Induction of Fas-Mediated CD4 T Cell Apoptosis by DC
The concept that the putative lymphoid-related CD8⁺ DC lineage may have a regulatory role, specifically killing the CD4 T cells they activate via Fas-mediated apoptosis, was introduced by Süss and Shortman [86]. The CD8⁺ DC subpopulation of mouse spleen was found to express high levels of a ligand binding a Fas-Fc construct. These splenic CD8⁺ DC gave a reduced proliferative response from allogeneic or antigen-specific CD4 T cells in culture, compared to the CD8^– DC. Apoptotic T cells were found in cultures stimulated with CD8⁺ DC, but not in those stimulated with CD8^– DC. However, if Fas-mutant lpr CD4 T cells were used, the proliferative response to the two DC subpopulations was identical, demonstrating that the difference was due to the Fas-signaled T cell apoptosis, and not due to differences in the stimulatory or antigen-presentation capacity of the DC. However, the view that a lymphoid-related lineage is specialized for this regulatory role must now be modified. FasL expression has been demonstrated in the presumed myeloid-derived DC generated in GM-CSF-stimulated cultures [87], and most DC subpopulations from mouse lymphoid tissue express a FasL at high levels if incubated overnight in culture (Mavaddat, unpublished data). All murine DC may have the capacity to express FasL during the course of an immune response and so limit the extent of CD4 T cell expansion. To date FasL has not been demonstrated on the surface of human DC.

Regulation of T Cell Cytokine Production by DC
A second functional difference between the DC subpopulations of mouse spleen is in the level of cytokine production by the T cells they activate. This was originally detected as a more extended period of proliferation from CD8 T cells when activated in culture by CD8^–, compared to activation by CD8⁺ DC; this proved to be the consequence of a much higher endogenous IL-2 production by T cells when activated by CD8^– DC [88]. The signals determining the level of IL-2 production differ from the signals for T cell proliferation, which are equivalent in the two DC subsets. This signaling difference between the myeloid-related and lymphoid-related DC cannot so far be ascribed to any of the known costimulatory molecules, or to DC-produced cytokines (Winkel and Kronin, in preparation). The use of CD8 null mice has demonstrated that this cytokine regulation does not involve negative "veto" signals from the CD8 molecule itself [89].

Differences in Cytokine Production by DC
Although none of the previous "regulatory" effects of DC could be ascribed to cytokines produced by one DC type and not the other, this remains a potentially important biological difference between DC lineages. Pulendran et al. (submitted) have recently detected a 50-fold difference in IL-12 production between the CD11b^low, putative lymphoid-related DC and the CD11b^high, putative myeloid-derived DC, both isolated from the spleens of Flt3L-treated mice. The production of IL-12 by DC may in turn be inhibited if DC mature in the presence of IL-10 [90]. The level of IL-12 production by DC could potentially affect the subsequent differentiation of activated T cells, higher levels of IL-12 favoring the Th1 over the Th2 cytokine orientation [91].

Differences between the DC of Different Organs
The DC of the thymus differ functionally from most of those in the periphery, since, as discussed earlier, they mediate the death of any self-reactive T cells rather than initiating a response to foreign antigens. They might therefore be armed with a mechanism to kill T cells which recognize the antigens they present. However, the surface level of the Fas-binding ligand on thymic DC is lower than on the corresponding CD8⁺ DC subpopulation of the spleen, and Fas-mediated killing of activated T cells is less with the thymic than the splenic DC (Mavaddat and Süss, unpublished data). In addition, studies with Fas mutant lpr mice have demonstrated that negative selection in the thymus can proceed in the absence of Fas-mediated apoptosis [92]. It is possible another specialized signaling system on thymic DC initiates the death of self-reactive cells. The alternative interpretation, supported by the experiments of Matzinger and Guerder [93], is that it is not the nature of the thymic DC but rather the immature state of the thymic T cells that leads them to die rather than proliferate in the thymus. Thus the "functional specialization" of thymic DC may only be a consequence of their anatomical location and the developmental state of the T cells they encounter.

The DC derived from precursors within the liver have been proposed as mediators of donor tissue tolerance after liver transplantation, since DC chimerism is a feature of long-term transplant survival [47]. Again, this suggests that liver DC might be armed with a system to inactivate tissue reactive T cells. However, the mechanisms proposed to date involve induction of T cell anergy as a consequence of encounters with immature DC, which present antigen but not costimulator molecules. Such a mechanism would not be a specialization of the liver DC lineage itself, but rather a consequence of the ability of the liver to continuously generate from endogenous precursors a supply of immature DC.

Interactions between DC and B Cells
Although T-dependent primary B cell activation is known to be dependent on DC [10, 11, 13, 14, 23, 94], there had been little consideration of the possibility that the DC might be specialized for interaction with the B cell as well as the T cell component. Recently, in studies using human cells and a system where the helper T cell signal was provided by CD40L transfected L cells, it has been demonstrated that culture-generated DC can directly modulate all stages of the B cell growth and differentiation [95, 96]. DC enhanced CD40L dependent B cell proliferation (three- to sixfold) and in the absence of added cytokines DC enhanced the differentiation of CD40-activated memory B cells to antibody secretion (100-fold increase in Ig). Furthermore, in the presence of DC and IL-2, naive sIgD⁺ B cells produced large amounts of IgM; this effect was dependent on the release of soluble mediators by the DC after CD40 engagement [95]. In addition, in the presence of IL-10, DC had the striking effect of stimulating CD40-activated naive sIgD⁺ B cells to express on their surface and secrete large amounts of IgA [96].

Many of these interactions with B cells may be a feature of a particular DC lineage. Recently, DC have been identified within germinal centers, as well as in the T cell areas of lymphoid tissue [97]; these interactions between DC and B cells might occur within the B cell follicles and involve specialized "GCDC." The induction in culture of IgM production in the presence of IL-2, mentioned above, is effected by the DC derived in culture from CD14⁺ intermediate precursors, but not by the LC-like DC derived from CD1a⁺ intermediate precursors [98]. Thus the different pathways of DC development in Figure 1 may be linked to a functional specialization of the end-product mature DC. The LC DC type may be mainly involved in cell-mediated immune responses, as supported by the participation of LC in delayed-type hypersensitivity reactions after hapten application on the epidermis. In contrast, the CD14⁺ precursor-derived DC, related to monocyte-derived DC and potentially located in tissues such as the dermis, or in blood, may, after antigen capture, migrate to the B cell follicles where they would be involved in the regulation of B cell humoral responses.

	Conclusions

Top Abstract Introduction The Langerhans' Cell Model... Does the LC Model... Thymic DC The Development of Myeloid... Lymphoid-Related DC in Mice Lymphoid-Related DC in Humans Functional Differences Between... Conclusions References

 
The field of DC research, after a long fallow period, is now rapidly expanding. However, it is still at an early stage, corresponding to the investigation of T and B lymphocytes some 20 years ago. DC are more heterogeneous than originally thought. The diverse pathways by which DC arise are now beginning to be mapped using the cell culture and cell transfer approaches traditionally used for other hemopoietic lineages, together with newer approaches employing genetically modified mice. Although the issue of myeloid versus lymphoid origin for particular DC populations leads to an interesting debate spiced with controversy, the more important point is that there are separate pathways of DC development with different regulatory systems. Different populations of DC display functional specializations that extend beyond the basic capacity to present antigen and activate T cells. Some linkages between the lineage origin and the functional specialization of DC have been made, but more information is needed to form a consistent model. We have presented an emerging picture of the DC system, one that highlights some intriguing new directions but one that will undoubtedly be modified and clarified by research that is already underway.

	Acknowledgments

 
We thank our colleagues past and present who have contributed to the research and to the ideas in this review. Special thanks to the following: in Melbourne, Australia: L. Wu, D. Vremec, G. Süss, V. Kronin, K. Winkel, N. Mavaddat, M. Krummel and D. Metcalf; in Dardilly, France: J. Banchereau, B. Dubois, J. Fayette, S. Vandenabeele, F. Brière; and elsewhere: C. Ardavin, E Maraskovsky, K. Georgopoulos, R. Steinman and K. Inaba.

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Top Abstract Introduction The Langerhans' Cell Model... Does the LC Model... Thymic DC The Development of Myeloid... Lymphoid-Related DC in Mice Lymphoid-Related DC in Humans Functional Differences Between... Conclusions References

 

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