Dendritic cells (DC) play key rolls in adoptive immunity, inducing antigen-specific immunity or tolerance. The functions of DC depend on DC subsets as well as their location or activation status. Understanding developmental lineages, precursors and inducing factors of each DC subset would help generating and/or activating "appropriate" DC subset in vitro or in vivo as a potential treatment for various diseases such as cancers and autoimmune diseases. However, despite extensive efforts, the precise developmental lineage, precursors of various DC, including skin Langerhans cells (LC), remain unclear and complex.1 Although the ultimate goal would be to comprehend ontogeny of human DC, most findings of human DC ontogeny is considerably based on in vitro cell culture assay using limited hamatopoietic cell populations. Meanwhile in animal models, we can utilize in vivo labeling assay, reconstitution assay using wide variety of cell populations or various targeted gene knockout mice etc, findings of which have greatly contributed to understanding of DC ontogeny in vivo. Therefore, this review is mainly based on in vivo findings from animal studies, combined with those of in vitro (human and animals), although one could argue whether experimental techniques like donor cell reconstitution in irradiated recipients truly reflects normal DC differentiation in steady-state.

Because of their many functional similarities to macrophages, DC and epidermal LC, were originally thought to be of myeloid lineage, an idea supported by studies demonstrating DC generation from monocytes using granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin (IL)-4 in vitro,2 or that phagocytic monocytes could differentiate into DC in vivo.3 Considerable evidence also suggested the existence of lymphoid-lineage DCs because CD8⁺ thymic DC could be generated from CD4^low early thymic precursors in vivo when intrathymically transferred.4 Other studies further confirmed and extended the concept that CD8⁺DC are of lymphoid origin5, 6 (and CD8^-DC are of myeloid origin). However, the simple concept was soon challenged by several studies where generation of both CD8⁺ and CD8^-DC subsets from either lymphoid-,7, 8 or myeloid-committed progenitors8 had been demonstrated in vivo.

All the DC subsets can uptake antigens and present them to T cells, but the detailed functions in immunity varies considerably, depending on the subset and presence/absence of inflammatory stimuli such as viral or bacterial infections. This review will focus on the following DC subsets (Table 1), discussing their developmental lineages and precursors.

The first DC category is termed as conventional DC. In mice, these DC can be divided into two subsets, CD8⁺- and CD8^-DC.9 CD8⁺ and CD8^-DC preferentially activate T cells toward Th1 and Th2 differentiation,10 respectively. The CD8⁺DC constitutively cross-presents antigens to T cells, while CD8^-DC will do so upon their activation.11 These conventional DC reside within lymph nodes, spleen, thymus, but not in bone marrow (BM).12 In thymus, most of the resident DC express CD8 and there is only small CD8^-DC population,13 as compared to those of other organs. The question of whether these conventional DC subsets are developmentally distinct populations from each others or are merely presenting different maturation/differentiation steps will be discussed later.

Plasmacytoid DC is characterized by the round shape, plasmacytoid morphology and remarkable ability to secret copious amount of interferon-γ in viral or bacterial infection,14-16 while they can also exhibit tolerogenic potential when not stimulated.17 They reside within lymph nodes, spleen, thymus, and BM,18-20 but the BM-plasmacytoid DC population does not seem to be developmentally equal to those of other organs since the BM-plasmacytoid DC population are capable of differentiating into conventional DC subsets.21 Thus, some of plasmacytoid DC populations, as do monocytes, can serve as pre-DC (Immediate DC precursor) for conventional DC subsets, which will be discussed later.

Epidermal LC, the primary sentinels of the skin, is the first described DC subset, which can be characterized by the Langerin expression and cytoplasmic Birbeck's granules. Upon activation (and constitutively to some extent), epidermal LC migrate through dermis into regional lymph nodes to present antigens to T cells.22 Therefore, this type of DC is categorized as "migratory DC"�D Other non-lymphoid tissue residing DC, such as dermal- and intestinal DC, both of which are not discussed in this review, would also fall into this category. In steady-state condition, LC have much long life span (labeled only -25% of LC after 2weeks) while most of other DC in other organs are labeled approximately by 3-10 days23 Epidermal LC appear to self-renew themselves within skin and are hardly repopulated by circulating precursors unless their residing environment is disturbed.24 Although LC cross-present viral antigen inefficiently (as compared to dermal DC),25 a very recent study identified their potential contribution against HIV infection,26 revealing the biological functions of Birbick granules for the first time. Possible tolerogenic capacity of LC have also been indicated.27, 28

There has been considerable evidence which suggest that DC subsets may associate with differentiation of T helper 1 cells (Th1)-, Th2-, Th17- or regulatory T cell (Treg) in a subset specific manner. As partially mentioned elsewhere, murine CD8⁺- and CD8^-DC appear to intrinsically induce Th1 and Th2, respectively.10 However, it has been shown that tumor cells can convert CD8^-DC (or termed CD11b⁺ myeloid DC) to induce Treg29 or that CD11b⁺ myeloid DC subset induces Th17 much more efficiently than other DC subsets in experimental autoimmune encephalomyelitis.30 CD11b⁺ myeloid DC can also induce Th1 when generated with GM-CSF and activated with LPS.31 Plsasmacytoid DC show tolerogenic potential17, 32 but can also induce Th1.31, 33 In humans, DC subsets seem to be less heterogeneous and two distinct DC subsets are known to exist: CD11c⁺CD14^-CD1a⁺ myeloid DC (mDC) and CD11c^-BDCA2⁺CD123⁺ plasmacytoid DC.34 Human mDC and (the descendent of) plasmacytoid DC used to be termed DC1 and DC2 respectively, because the mDC and plasmacytoid DC were shown to preferentially induce Th1 and Th2, respectively.35 However, the human DC1/DC2 concept was soon challenged by studies in which human plasmacytoid DC was shown to be able to induce Th1 response.36, 37 Furthermore, human plasmacytoid DC can also induce T reg.38 LC was thought to induce Th1 because of its ability to produce bioactive IL-12, evidenced by a study using human LC.39 However, LC has recently been shown to induce Th240 or to have a regulatory function in mice.27 Overall, although there is a "tendency" of DC lineage- or subset-specific Th- or Treg induction, such induction is also highly dependent on the experimental condition or environmental factors such as cytokines, chemokines, stimuli through various Toll like receptors,41 In other words, Th- or Treg differentiation by DC/LC depends on how they are generated/developed, matured or activated.

All the DC subsets, like other hematopoietic cells, ultimately derive from hematopoietic stem cells (HSC). HSC self-renew themselves and can differentiate into myeloid- and lymphoid-committed hamatopoietic precursors (and other lineages like erythrocyte or megacaryocyte) (Fig. 1). In lymphopoiesis, common lymphoid progenitor (CLP)42 used to be thought as the governing lymphoid-committed progenitor which could give rise to all the lymphoid lineages such as T cells and B cells. The CLP is characterized by its IL-7 receptor (R)-α expression, together with other hematopoietic progenitor markers such as c-kit and Sca-1. IL-7Rα knockout mice exhibited significantly impaired lymphopoiesis, supporting the idea of CLP might be a vital precursor for lymphopoiesis.43 However, the current schema of hamatopoiesis is a little more complex. Other, more potent thymus repopulating progenitors, called early T-lineage progenitor (ETP) and the precursor have been identified within thymus44 and BM45 both of which are negative for IL-7Rα expression. Furthermore, earliest lymphoid progenitor (ELP)46 have been identified and is supposed be in upstream of other lymphoid progenitors from the characteristics (c.f. ELP remains to have myeloid lineage potential). As for myeloid-lineage, common myeloid progenitor (CMP)47 and their progeny (granulocyte-monocyte progenitor and monocytes etc) appear to be only myeloid-committed DC precursors. DC which are generated through these committed-precursors would be lymphoid- or myeloid-lineage DC. Indeed, some of plasmacyotid- and thymic DC (but not splenic DC, regardless of their CD8 expression) in normal mice have IgH D-J rearrangement,48 which is a trace of lymphoid lineage.49 Such location dependence of IgH rearrangement in DC might be because lymphoid- (thymic precursor) and myeloid progenitors are simply abundant in thymus and spleen, respectively, and because plasmacytoid DC population is initially generated in BM where precursors of both lineages (CMP and CLP etc) are abundant. The finding of lymphoid trace of steady-state DCs in normal mice may provide evidence that DC have both lymphoid- and myeloid origin in vivo, in addition to those obtained from cell transfer studies. The development of DC seems to be quite flexible since at least two distinct developmental pathways exist to form a particular DC subset. Then one might wonder if there are any other pathways for DC generation. There was a report indicating a common DC precursor population,50 but the study was confounded by contamination of more than two populations.51 So far, current findings have not achieved a clear consensus for such DC-restricted pathway yet.

Human monocytes are first shown to differentiate into DC when cultured with GM-CSF+IL-4,2 and can have some of LC characteristics when transforming growth factor (TGF)-β is added to the cytokine combination.52 Human CD34+ cells (HSC-enriched population) can differentiate into DC or LC when cultured with GM-CSF and tumor necrosis factor (TNF)-α,53 IL-3 and TNF-α,54 or FMS-like tyrosine kinase-3 (FIT3) ligand (L) and TGF-β.55 Mouse BM cells can differentiate into DC/LC when cultured with GM-CSF+TNF+stem cell factor (SCF),56 or into plasmacyotoid-, CD8⁺- and CD8^-DC when cultured with FLT3L.57, 58 There is an interesting report showing the importance of GM-CSF (+SCF) and IL-7 for DC generation from CMP and CLP in vitro, respectively.59 Mouse spleen cells can differentiate into DC when cultured with GM-CSF+FLT3L (or+SCF).60 Mouse thymic precursor populations can differentiate into thymic DC when cultured with IL-7-cytokine mix (+ IL-3) without GM-CSF, the myeloid lineage growth factor.61 (Table 2)

From these findings, GM-CSF, IL-7 or FLT3L appears important for DC generation in vitro. The starting material tends to be cell populations which could be obtained from peripheral blood in human studies because of its easier access in many aspects, while cell preparations from various lymphoid organs are popular in murine studies, which makes direct comparison difficult between human and mouse studies.

In vivo cell transfer studies have significantly contributed to the understanding of DC lineages. Unlike the case of in vitro studies, where many myeloid-differentiation of DC had been shown, the first in vivo evidence of DC differentiation in vivo was that of lymphoid-lineage. A study demonstrated that thymic precursor population (with lymphoid-restricted differentiation capacity) can give rise to DC and T cells when intrathymically transferred.4 Meanwhile, the first evidence of myeloid-lineage DC differentiation in vivo was given later in a study where phagocytic monocytes differentiated into DC.3 Generation of both CD8⁺- and CD8^-DC have been shown after intravenous transfer of lymphoid-committed (CD4^low thymic precursor7 or CLP8) or myeloid-committed precursor (CMP8), which have challenged the CD8⁺DC = lymphoid-lineage DC concept. Generation of plasmacytoid DC from FLT3⁺ fractions of both CLP and CMP has also been shown.62 In the case of LC, LC differentiation through lymphoid-lineage (thymic precursor63 and CLP64) and myeloid-lineage (CMP64 and BM monocyte precursor65) has been shown in vivo. (Table 3) Overall, these in vivo cell transfer studies have suggested the DC develop through both lymphoid- and myeloid pathways, indicating the developmental flexibility of DC. CLP is more potent than CMP at DC generation in a per cell basis, but since there is an excess of CMP over CLP in BM,66 perhaps both the committed-progenitors significantly contribute to DC generation as a whole. Interestingly, most of the DC precursor populations have receptors such as GM-CSFR, IL-7Rα, FLT3 or c-kit (SCFR), reflecting the findings of cytokine requirement in in vitro studies.

The findings in knockout mice are complicated (Table 4). The data from knockout mice that show hematopoietic lineage restriction has been thought to readily indicate DC lineages. For example, Ikaros DN mice have showed significantly impaired lymphoid development and absence of certain DC subsets (splenic CD8⁺- and CD8^-DC and thymic CD8⁺DC),67 by which these absent DC subsets are considered to be of lymphoid lineage. However, there have been many inconsistent findings in other knockout mice that also show impaired lymphopoiesis, such as mice deficient for Ikaros C68 or Common γ-chain69 where development of only limited (only CD8^-DC) to no DC subsets are affected. Furthermore, CD8^-DC is absent in Relb knockout mice70 where myeloid hyperplasia is observed, while the same CD8^-DC subset is again absent in PU.1 knockout mice where development of B- and myeloid lineage is deficient.71, 72 Meanwhile, plasmacytoid DC and CD8⁺DC are absent, accompanied with defective myeloid development in mice deficient for ICSBP (IRF8),73, 74 which form transcription complexes with PU.1. These findings might simply indicate complicated regulation of lymphopoiesis, but they might as well indicate the existence of indispensable differentiation factor for certain DC subsets regardless of their passed lineages. At least the absence of LC in TGF-β knockout mice,75 which have normal development of both lymphoid- and myeloid-lineage, probably favors the latter idea. LC are also absent in mice deficient for Id2,76 a transcription factor regulated by TGF-β, or Runx377 which mediates TGF-β responses. Meanwhile, LC and monocytes are absent in macrophage colony-stimulating factor (M-CSF) R knockout mice,65 which may provide evidence that LC are of myeloid lineage. Paradoxical finding is that GM-CSFR knockout mice show normal DC development78 or that IL-7Rα knockout donor cells can reconstitute various DC subsets, including epidermal LC, in lymph nodes, spleen, thymus or BM.79 However, given the developmental flexibility of DC, the absence of signals in a DC differentiation pathway would have been compensated by those of the other pathways. Absence of these cytokines (GM-CSF or IL-7 etc) appears to be compensated by FLT3L,57, 58 although addition of GM-CSF to FLT3 improves yields of DC as compared to those with either cytokine alone.80 The FLT3 knockout mice show low DC numbers81 as do mice deficient for STAT3,82 which is a key factor in FLT3 signal cascade. Furthermore, FLT3L exceptionally increase DCs in mice83 and human84 when systemically administered.

Distinct DC subsets possess different functions, but their developmental independency is not perfectly clear. As previously mentioned, plasmacytoid DC has been shown to be able to differentiate into conventional DC.85 Thus, plasmacytoid DC, at least those in bone marrow, can serve as pre-DC for cDC in an inflammatory condition. Many pre-DC populations, or immediately DC precursors, have been identified so far in blood, spleen and BM (Table 5). In BM, a pre-DC called "pre-immunocyte" (B220⁺CD11c⁺CD31⁺Ly-6C⁺)86 has been found to generate immature DC and macrophage under aegis of M-CSF or GM-CSF and also to generate both CD8⁺- and CD8^- conventional D in thymic organ culture. In addition, the pre-immunocyte population immediately produce high level of interferon-α mRNA as do plasmacytoid DC. A few years later, 2 phenotypically distinct populations (B220⁺CD11c⁺MHCII^-Gr-1⁺M-CSFR^- and B220^-CD11c⁺MHCII^-Gr-1^-M-CSFR^int)87 have been identified. The B220⁺ pre-DC give rise to both plasmacytoid DC, conventional DC, while the latter B220^- pre-DC give rise to only conventional DC. From the surface phenotype and generating DC subsets, the former population might be equal or closely related to the pre-immunocyte population. BM-monocyte population (Ly-6C^highCD11b⁺CD11c^-B220^-CD24^int)88 also differentiate into splenic conventional DC, although repopulating only very small percentage (2%) of total splenic DC. Recently, a group identified a much more efficient splenic DC-repopulating population within spleen, called "intrasplenic pre-cDC" (CD11c^intCD45RA^lowCD43^intSIRP-α^intCD4^-CD8^-MHC II^-).89 The intrasplenic pre-cDC repopulates splenic DC in steady-state most efficiently while monocyte populations hardly do so. The pre-cDC population does not respond M-CSF, therefore they appear different from monocytes. Blood- or splenic monocytes (Ly-6C^low CD11b⁺NK1.1^-SSC^low) can give rise to splenic DC in inflammatory conditions, but they form only a distince (CD8^-) DC population. Since most of known pre-DC (plasmacyitoid DC or monocytes) differentiate into DC with inflammatory stimuli or inflammatory growth factors such as GM-CSF. Although there have been many studies using monocyte-derived or GM-CSF-induced DC, these protocol might not be suitable to examine DC functions in steady-state, or tissue-residing DCs.

Incidentally, it has been reported that CD8^-DC can differentiate into CD8⁺DC,90 indicating precursor-progeny relationship between the two conventional DC subsets. However, this might be because of the existence of direct CD8⁺DC precursor (but yet negative for CD8 expression) within CD8^-DC population like others pointed.91

As mentioned, the DC development is complex and quite flexible, unlike other hamatopoietic lineages like T-, B-, NK cells, neutrophils or monocytes etc. One might wonder why such flexibility exists in DC development. The speculations here are as follows. The flexibility might simply be a redundant mechanism to maintain the important hamatopoietic populations, DCs, in any situations. Alternatively, since the existence of tissue-residing DC and their functions are relevant in various lymphoid organs (thymus, lymph nodes, spleen etc) or in non-lymphoid organs (skin, gut etc) to induce immunity and/or tolerance (such that within thymus),92 it would be advantageous for a DC subset to be able to differentiate in situ from certain "available" precursors such as organ-seeding- or self-repopulating populations in the organ according to the required functions (or DC subset), irrespective of the committed-lineages of DC precursors.

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