Development of Dendritic-Cell Lineages

Immunity

Reviews Development of Dendritic-Cell Lineages Li Wu1,* and Yong-Jun Liu2,* 1

Immunology Division, The Walter & Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3050, Australia Center for Cancer Immunology Research, M.D. Anderson Cancer Center, 7455 Fannin, Unit 901, Houston, TX 77030, USA *Correspondence: [email protected] (L.W.), [email protected] (Y.-J.L.) DOI 10.1016/j.immuni.2007.06.006

2

Dendritic cells (DCs) are a heterogenous population of bone-marrow-derived immune cells. Although all DCs share a common ability to process and present antigen to naive T cells for the initiation of an immune response, they differ in surface markers, migratory patterns, localization, and cytokine production. DCs were originally considered to be myeloid cells, but recent findings have demonstrated that DCs can develop not only from myeloid- but also from lymphoid-committed progenitors. The common feature of the progenitors capable of developing into DCs is the surface expression of Flt3 receptor. The development of different populations of DCs is differentially regulated by various transcription factors and cytokines. This review summarizes the recent advances made in the field of DC development.

Introduction Dendritic cells (DCs) are antigen-presenting cells crucial for the innate and adaptive immune response to infections and for maintaining immune tolerance to self-tissues (Banchereau and Steinman, 1998). DCs represent a sparsely distributed population of bone-marrow-derived cells. Although they share many common features, multiple subtypes of DCs with distinct life span and immune functions have been identified (Shortman and Liu, 2002; Shortman and Naik, 2007). The DC subtypes found in a steady-state mouse and in human include type-1 interferon-producing plasmacytoid DCs (pDCs) and the conventional DCs (cDCs) in the nonlymphoid tissues, in the circulation, and in lymphoid tissues. The resident cDCs in lymphoid tissues include cDCs present in the thymus, spleen, and lymph nodes and consist of phenotypically different subtypes. cDCs can also be divided into subsets according to their tissue localizations, such as skin DCs including Langerhan’s cells (LCs) in epidermis and dermal DCs in dermal areas; mucosal tissue-associated DCs; lymphoid tissueassociated DCs including splenic marginal zone DCs, T cell zone-associated interdigitating cells, germinal center DCs, and thymic DCs; and interstitial tissue DCs including liver DCs and lung DCs. Tissue microenvironments appear to have major impact on the function of the residential DCs. In addition, DCs that are not found in the steady state but develop after infection or inflammation include the monocyte-derived DCs and the tumor necrosis factor (TNF)-producing and inducible nitric oxide synthase (iNOS)-expressing DCs (Geissmann et al., 1998; Naik et al., 2006; Randolph et al., 1999; Serbina et al., 2003). Here we review the recent progress on the development of DC subsets. Ontogeny of DCs In mice, DCs can be detected in the thymus as early as at embryonic day 17, coinciding with the emergence of CD4+CD8+ thymocytes and the beginning of thymocyte

selection processes. Thereafter, the number of DCs and thymocytes increases rapidly in parallel. The majority of cDCs at this early stage are CD8 , with the emergence of CD8+ DC observed at 1 week after birth. The CD8+ population becomes the major population by 2 weeks of age, with the relative proportions of each subset similar to those found in the adult thymus (Dakic et al., 2004). The pDCs appear at the same time as cDCs in the thymus, and their numbers increase with age and in parallel with the increase in the number of cDCs. A substantial number of DCs can be detected in mouse spleen on day 1 after birth (Dakic et al., 2004; Sun et al., 2003). The absolute numbers and proportion of both cDC and pDC do not reach adult amounts until 5 weeks of age. During this period, the composition of the cDC populations changed markedly. In contrast to the cDCs found in an adult spleen that contains the CD8+CD205+ (25%) and CD8 CD205 (75%) populations, in the spleen of a day 1 newborn mouse, the CD8 CD205 cells represent a minor cDC population, whereas the dominant cDC population is CD8 that also express CD205 (CD8 CD205+). Moreover, this CD8 CD205+ cDC subset has the capacity to produce IL-12p70, a cytokine normally produced by the CD8+CD205+ cDC in adult spleen (Dakic et al., 2004; Sun et al., 2003). Interestingly, at 3 weeks of age, the CD8 CD205+ population becomes undetectable and the CD8+CD205+ cDCs become the major cDC population with the capacity to produce IL-12p70, although at a relatively lower amount than their adult counterpart, whereas the CD8 CD205 cDCs remain as a minor population. At the young adult stage (6 weeks), the ratio of the CD8 CD205 and CD8+CD205+ cDCs changes substantially, with the CD8 CD205 cDCs becoming the dominant population. These phenotypic and functional changes suggest that the neonatal CD8 CD205+ DCs represent an immature stage of the CD8+CD205+ cDC population found in adult mouse spleen and that different DC populations have different developmental kinetics during ontogeny. Immunity 26, June 2007 ª2007 Elsevier Inc. 741

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Reviews Figure 1. A Developmental Scheme of Mouse DC Development from BM Hemopoietic Stem Cells and Lineage-Committed Progenitors Both cDC and pDC can be generated from the Flt3 expressing early myeloid or lymphoid progenitors. Flt3L is essential for the development of steady-state DC populations. Under inflammatory conditions, i.e., in the presence of GM-CSF, monocytes can differentiate into cDC. Abbreviations: HSC, hemopoietic stem cell; MPP, multipotent progenitors; CMP, common myeloid precursors; CLP, common lymphoid precursors; GMP, granulocyte and macrophage precursors; MEP, megakaryocyte and erythrocyte precursors; M-DC, macrophage and DC precursors.

Consistent with the developmental kinetics of DC during mouse ontogeny, functional analysis of neonatal DC have shown that they are immature in a number of different functions including cytokine production and antigen presentation (Dakic et al., 2004; Muthukkumar et al., 2000; Ridge et al., 1996; Sun et al., 2003; Vollstedt et al., 2003). In humans, MHC class II-expressing DC-like cells can be detected in the yolk sac and mesenchyme as early as 4–6 weeks of gestation, which preceded the formation of liver, bone marrow, and thymus (Janossy et al., 1986). These MHC class II-expressing DC-like cells appear in the thymic medulla and paracoritcal area of mesentery lymph nodes at 11–14 weeks, nonlymphoid tissues except brain at 12 weeks, bone marrow at 14–17 weeks, the T zone of spleen at 16 weeks, and fetal skin and tonsillar crypts at 23 weeks of gestation (Janossy et al., 1986; Hofman et al., 1984). Little is known on the ontogeny of human pDCs, although pDCs can be detected in fetal thymus and liver (Y.-J.L., unpublished observation). Myeloid Origin of DC DCs were originally considered to have a myeloid origin. Early studies demonstrated that mouse BM myeloid precursors had a capacity to produce macrophages, granulocytes, and DCs in the presence of granulocyte-macrophage colony-stimulating factor (GM-CSF) (Inaba et al., 1993). Similar development was found in the studies of human cells where a CD34+ BM-derived precursor differentiated into CD1a monocytes, a granulocyte-precursor population, and a bipotential precursor population with the ability to produce mature DC when cultured in the presence of GM-CSF and TNF-a or macrophages when cultured in the presence of M-CSF (Reid et al., 1992; Szabolcs et al., 1996; Caux et al., 1996). Further evidence for a myeloid origin of DC came from the finding that mono742 Immunity 26, June 2007 ª2007 Elsevier Inc.

cytes differentiate into DCs in the presence of GM-CSF and IL-4, in vitro (Romani et al., 1994; Sallusto and Lanzavecchia, 1994; Akagawa et al., 1996; Kiertscher and Roth, 1996; Pickl et al., 1996; Zhou and Tedder, 1996; Chapuis et al., 1997). This differentiation process also occurs in vitro when monocytes reverse transmigrate in an ablumenal-to-lumenal direction across endothelial cells (Randolph et al., 1999). A similar phenomenon has been observed in vivo with subcutaneous tissue monocytes (Figure 1; Randolph et al., 1999). Direct evidence for a myeloid origin of DC came from studies demonstrating that the transplantation of mouse BM common myeloid progenitors (CMPs) into irradiated recipients led to the reconstitution of the cDCs and pDCs in the spleen and thymus (Traver et al., 2000; Wu et al., 2001; Manz et al., 2001a). Further studies demonstrate that the CMPs are heterogenous in Flt3 expression, and it is the Flt3+ fraction of CMPs that is able to produce all cDC and pDC subsets found in the mouse spleen and thymus (Figure 1; D’Amico and Wu, 2003). In addition, a CX3CR1+CD117+ clonogenic progenitor that can give rise to macrophages and splenic-resident cDCs but not pDC has been identified from mouse BM (Fogg et al., 2006). This progenitor may represent a common precursor for macrophage and cDCs downstream of the CMP and the branch point of pDC differentiation. Lymphoid Origin of DC Early studies on the lymphoid tissue-resident DCs demonstrate that thymic cDCs and subpopulations of cDC in mouse spleen and LNs express markers associated with lymphoid cells, including CD8a, CD4, CD2, BP1, and CD25 (Vremec et al., 1992). This finding suggests that some DCs may have a lymphoid origin. The first direct evidence for a lymphoid origin was provided by studies showing that the transfer of intrathymic lymphoid-restricted precursors

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Reviews expressing low CD4 into the thymus of irradiated recipients give rise to both T cells and CD8+ thymic cDCs (Figure 1; Wu et al., 1995; Ardavin et al., 1993). This precursor was also shown to have the potential to produce both CD8+ and CD8 splenic cDC when injected intravenously and to be devoid of myeloid potential (Wu et al., 1996, 2001; Martin et al., 2000). Subsequent studies of the mouse BM common lymphoid progenitor (CLP) also demonstrate the potential of these progenitors to differentiate into DCs both in vitro and in vivo (Wu et al., 2001; Manz et al., 2001b; Izon et al., 2001). Although a bias toward producing the CD8+ DC population was observed, the CLP displayed the capacity to give rise to all splenic and thymic DC subsets (Wu et al., 2001; Dakic and Wu, 2003). Thus, evidence for a lymphoid origin of DCs has been firmly established. The fact that both the CMP and CLP are capable of giving rise to all DC subtypes of the spleen and thymus not only demonstrates that DCs can be of either myeloid or lymphoid origin, but also indicates that the phenotype of the DCs is not a reflection of its lineage origin. Origin of pDCs It was initially suggested that pDC (also known as interferon-producing cell, IPC) is of lymphoid origin, based on the finding that human pDCs express many lymphoid markers, including germline IgK and pre-T cell receptor (Grouard et al., 1997; Rissoan et al., 1999) but do not express myeloid markers. In addition, mouse pDCs were found to express the Rag gene and harbor IgH D-J rearrangement (Corcoran et al., 2003; Shigematsu et al., 2004; Pelayo et al., 2005). Two separate studies further support the lymphoid origin of pDC in human and mice. First, overexpression of the dominant-negative transcription factors Id2 or Id3 in human CD34+ hematopoietic progenitor cells blocks development of pDC, T cells, and B cells, but not myeloid DC (Spits et al., 2000). Second, knockdown of Spi-B, a hematopoietic-specific Ets family transcription factor that is expressed exclusively in lymphoid cells, in human CD34+ hematopoietic progenitor cells strongly inhibits their potential to differentiate into pDC (Schotte et al., 2004). However, more recent studies revealed that Flt3+ cells within either CLPs or CMPs could differentiate into both cDC and pDC in cultures and in vivo (D’Amico and Wu, 2003; Chicha et al., 2004; Shigematsu et al., 2004). An interesting observation from the study of Shigematsu et al. was that although Rag expression and IgH D-J rearrangements were not detectable in CMPs, CMPderived pDCs express both Rag and IgH D-J rearrangement. The authors suggest that the expression of Rag and IgH D-J rearrangement does not necessarily reflect pDC lineage origin but is a result from the ‘‘ectopic expression’’ or ‘‘reactivation’’ of Rag and IgH D-J rearrangement during CMP differentiation into pDCs. Alternatively, because CMPs contain the Flt3+ progenitor population that is capable of differentiating into pDC, cDCs, and more interestingly B cells (D’Amico and Wu 2003), the pDCs derived from the Flt3+ fraction of CMPs could be the progeny of the precursors with potential for both pDC and B cell differentiation. If this is indeed the case, the question will be

where pDC, cDC, and B cells branch out from the Flt3+ progenitors, and what regulates this divergence. Development of DC from the Immediate Precursors A precursor that is at a developmental stage just before the formation of a phenotypically identifiable DC is termed immediate DC precursor. These precursors can be identified and isolated from mouse blood and have a capacity to differentiate into mature subsets of DCs in vitro. Two populations of DC precursors in mouse blood have been described (O’Keeffe et al., 2003). The CD45RA CD11cintCD11b+ population represents immature cDC that acquires the morphology of mature cDCs in the presence of TNF-a and the ability to stimulate T cells and to produce IL-12 in response to microbial stimuli. The CD45RA+CD11cloCD11b population represents the pDCs. These cells mature into cDC-like cells only in the presence of stimuli such as CpG and GM-CSF, weakly stimulate T cells in this matured state, and produce large quantities of type I interferon (Nakano et al., 2001; Martin et al., 2002; Asselin-Paturel et al., 2001). Thus, although this precursor DC population is able to differentiate into a cDC-like population of cells, their poor antigen-presenting capabilities make them distinct from the mature cDCs (Krug et al., 2003). The DCs in peripheral lymphoid organs are continually replaced by blood-borne precursors. A recent study reported that DCs in mouse spleen and LNs underwent a limited number of cell divisions in situ and could be entirely replaced within 10–14 days (Liu et al., 2007). Consistent with this finding, in situ cDC precursors (pre-DCs) with limited proliferation potential have been identified in mouse spleen and lymph nodes (Naik et al., 2006; Diao et al., 2006). These precursors were identified in mouse spleen as CD11cintCD45RAloCD43intSirp-aintCD4 CD8 and comprised 0.05% of splenocytes (Naik et al., 2006). When transferred into nonirradiated recipient mice, they differentiated into all splenic cDC populations with limited proliferation within 3–5 days, representing the most immediate cDC precursors identified to date. These pre-DCs are distinct from monocytes, because transfer of purified monocytes into a steady-state mouse did not generate significant number of cDC in the spleen. Monocytes can differentiate into splenic cDC only under a GM-CSF-mediated inflammatory condition (Naik et al., 2006). There are two major monocyte subsets that vary in chemokine receptor (CCR) and adhesion molecule expression and in migratory and differentiation properties. In humans, ‘‘classical’’ CD14+CD16 monocytes express CCR2, CD64, and CD62L, whereas ‘‘nonclassical’’ CD14loCD16+ monocytes lack CCR2. Their counterparts in mice are CCR2+Gr-1hi and CCR2 Gr-1lo monocytes, respectively. Gr-1hi (Ly6Chi) monocytes are recruited to inflammatory sites, e.g., inflamed skin or acutely inflamed peritoneum, and give rise to macrophages and DCs in inflammatory or infectious disease models and to epidermal LCs after skin inflammation. Gr-1lo monocytes have been proposed as precursors for steady-state DCs, but experimental evidence is as of yet limited (Tacke and Randolph, 2006). Immunity 26, June 2007 ª2007 Elsevier Inc. 743

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Reviews Table 1. Differential Requirement for Transcription Factors in DC Development cDCs DC Populations

CD4 CD8+

CD4+CD8

CD4 CD8

pDCs

Ikaros

+

+

+

+

IRF-2

+

+

IRF-4

+

+/

+/ +

+/

+a

+a

+a

nd

IRF-8

+

PU.1

+a

Id2

+

RelB

LCs

+/

+/

nd

+ a

+

+/

STAT3

+

+

+

nd

Gfi1

+

+

+

+

nd

The requirement of transcription factor for the development of each DC populations is presented as follows: +, required; not required; +/ , partially required; and nd, not determined. a A. Dakic, S. Nutt, and L.W., unpublished observations.

Transcription-Factor Regulation of DC Development Given that both myeloid and lymphoid precursors have the capacity to generate all lymphoid-resident DC subsets, the following questions still remain: how are the individual subsets delineated, and at what point in DC development is the commitment made to a subpopulation of DC? These questions have been partially addressed by studies on the roles of transcription factors in DC development. Growing evidence indicates that distinct DC subpopulations require different transcription factors during ontogeny (Table 1). The zinc finger transcriptional regulator Ikaros has been shown to play an essential role in DC development. Although a dominant-negative mutation in the Ikaros gene in mouse led to the ablation of all DC subsets, a null mutation in the Ikaros gene showed an absence of CD8 cDC and pDC and residual CD8+ cDC development (Wu et al., 1997; Allman et al., 2006). These studies demonstrate a requirement for Ikaros for the development of most cDC and pDC, which is consistent with the observation that Ikaros is required for the normal development of the early hemopoietic progenitors (Nichogiannopoulou et al., 1999). The first transcription factor identified as being important in subset delineation was RelB. RelB is a member of the NF-kB (Rel) family and was found to be expressed at higher amounts in CD8 cDC compared to CD8+ cDC in the spleen. Disruption of RelB gene resulted in the defective development of cDCs, especially the splenic CD4+CD8 DC subset, but not the CD4 CD8+ and CD4 CD8 DCs (Weih et al., 1995; Burkly et al., 1995; Wu et al., 1998; L.W., unpublished data). Consistent with these observations, mice lacking the TRAF6 transcription factor, believed to act upstream of the same signaling cascade of RelB, also show defects in CD4+CD8 cDC development (Kobayashi et al., 2003). The three interferon regulatory factors (IRF), namely IRF-2, IRF-4, and IRF-8 (also known as ICSBP), also play important roles in the development of different DC popula744 Immunity 26, June 2007 ª2007 Elsevier Inc.

,

tions. Mice lacking a functional IRF-2 or IRF-4 gene showed defects in the development of CD4+CD8 cDC, and IRF-4-deficient mice also showed defect in pDC subsets in the spleen (Suzuki et al., 2004; Ichikawa et al., 2004; Honda et al., 2004). In contrast, IRF-8 plays crucial roles in the development and function of CD4 CD8+ cDCs, pDCs, and LCs (Schiavoni et al., 2002, 2004). Further studies on mice with double deficiencies of IRF-4 and IRF-8 show defects in the development of all DC populations, suggesting a nonredundant role of each of the factors in the development of specific DC subsets (Tamura et al., 2005). Although these studies demonstrate the importance of these IRFs in DC development, further investigation is required to elucidate the molecular mechanisms. Id2, a member of the inhibitory helix-loop-helix (HLH) transcription factor family, is upregulated during DC development and is required for the development of CD4 CD8+ cDCs and LCs (Hacker et al., 2003). In contrast, overexpression of Id2 in hemopoietic stem cells inhibited the development of pDCs, indicating that Id2 acts as an inhibitor of pDC development (Spits et al., 2000). This inhibitory effect of Id2 in pDC development may be mediated by antagonizing the functions of activating HLH factors HEB and E2A, as indicated by the fact that overexpression of these factors in hemopoietic progenitors stimulated pDC development (Schotte et al., 2004). The ETS transcription factor Spi-B is expressed by pDCs, B cells, and CD34+ hemopoietic progenitors, but not by cDCs. The knockdown of Spi-B mRNA expression in human hemopoietic progenitors led to the defective development of pDCs, but stimulated the development of B cells and myeloid cells. These findings demonstrated that Spi-B functions as a key regulator of pDC development (Schotte et al., 2004). The transcription factor PU.1, another member of the ETS family that interacts with Spi-B, IRF-4, and IRF-8, is also required for the development of both cDCs and pDCs, as shown by the fact that impaired development of cDCs from the hemopoietic

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Reviews progenitors in the embryo or in neonatal PU.1-deficient mice (Guerriero et al., 2000; Anderson et al., 2000) and defective development of both cDCs and pDCs in the adult mice with induced deletion of PU.1 have been observed (A. Dakic, S. Nutt, and L.W., unpublished data). Distinct molecular-signaling pathways for the development of steady-state DC and the inflammation-induced DC differentiation have recently been distinguished. The transcription factor STAT3 is required for Flt3L-dependent steady-state DC development. Deletion of STAT3 in hemopoietic cells abolished the effects of Flt3L on DC development and led to a profound deficiency in the DC compartment in lymphoid tissues. In contrast, deletion of STAT3 did not affect DC development in vitro in the presence of GM-CSF, indicating that STAT3 is not required for GM-CSF-dependent inflammatory DC differentiation (Laouar et al., 2003). Moreover, the transcriptional repressor Gfi1 has been shown to control DC development through regulating STAT3 activation. Gfi1-deficient mice showed a global reduction of myeloid- and lymphoid-derived DCs in all lymphoid organs, whereas epidermal LCs were enhanced in number (Rathinam et al., 2005). Gfi1 also functions as a critical modulator of DC versus macrophage development (Rathinam et al., 2005). Cytokine Regulation of DC Development In addition to the transcription factors that differentially regulate the development of distinct DC subsets via different signaling pathways, several cytokines have been shown to differentially promote the growth and differentiation of different DC subsets. As mentioned above, Flt3L is a crucial factor in both human and mouse for promoting the development of both cDC and pDC in vivo and in vitro. However, a bias toward the generation of CD8+ cDC and pDC in the spleen has been observed in mice treated with murine Flt3L (O’Keeffe et al., 2002b; Bjorck, 2001). In contrast, treatment of mice with GM-CSF, a cytokine that promotes the differentiation of myeloid DC from the early hemopoietic progenitors and monocytes, promoted the development of the splenic CD8 cDC (O’Keeffe et al., 2002b). Studies have also shown that although GM-CSF and Flt3L both play a critical role in the development of cDC, only Flt3L is critical for the development of pDCs. In addition, GM-CSF promotes cDC development at the expense of pDC development mediated by Flt3L in vivo and in vitro (Maraskovsky et al., 1996; Pulendran et al., 2001; Blom et al., 2000; Gilliet et al., 2002; Naik et al., 2005). GM-CSF requires STAT5 to suppress Flt3L-driven pDC development from the lin Flt3+ bone-marrow progenitor population. In vivo, STAT5-deficient hematopoietic progenitors repopulate the pDC lineage preferentially relative to STAT5-sufficient progenitors. In contrast, STAT5 is necessary for maximal reconstitution of cDCs. STAT5 activation by GM-CSF rapidly attenuates the expression of critical pDC-related genes in lin Flt3+ bonemarrow progenitor cells cultured in Flt3L. GM-CSF therefore controls pDC development through a STAT5-dependent pathway that impinges upon the pDC transcriptional network, influencing the production of DC subsets from

the progenitor compartment (E. Esashi, Y.-H. Wang, O. Perng, X.-F. Qin, Y.-J.L., and S.S. Watowich, unpublished data). The cytokine TGF-b1 plays a critical role in LC development as demonstrated by the fact that the in vitro generation of LCs from CD34+ progenitors can be greatly enhanced by TGF-b1 (Caux et al., 1999). The TGF-b1deficient mice lacked LCs (Borkowski et al., 1996), but BM cells from TGF-b1-deficient mice could give rise to LC after transfer into lethally irradiated recipients. Thus, the LC defect in TGF-b1-deficient mice is not a result of deficiency in BM LC precursors; instead, TGF-b1 produced by non-BM-derived cells is required for the differentiation of LCs (Borkowski et al., 1997). It has been suggested that TGF-b1 exerts its effect through regulating the expression of its downstream transcription factor Id2, which is required for the normal development of LCs (Zenke and Hieronymus, 2006). Organ-Specific DC Populations in the Thymus The thymus is a primary lymphoid tissue where T cell differentiation and selection occurs and leads to the generation of naive CD4+ and CD8+ T cells with a diverse TCR repertoire, naturally occurring CD4+CD25+ regulatory T cells (Apostolou et al., 2002; Jordan et al., 2001; Watanabe et al., 2005), as well as some of the double-negative invariant T cell subsets, such as NKT cells (Benlagha et al., 2005; Tilloy et al., 1999) or mucosa-associated invariant T (MAIT) cells (Treiner et al., 2003). Thymus is also the site for central immune tolerance induction. Mouse thymus contains CD11cintCD45RA+ pDCs and two CD11chiCD45RA cDC subsets that can be segregated on the basis of CD8 and the signal regulatory protein-a (Sirp-a) expression, as CD8+Sirp-a and CD8 /loSirp-a+ cDC subsets (Lahoud et al., 2006). The CD8+Sirp-a subset representing 70% of thymic cDC is generated within the thymus from the earliest intrathymic progenitors, whereas the minor CD8 /loSirp-a+ cDC subset is originated from the peripheral migratory DCs (Donskoy and Goldschneider, 2003; A. Proietto and L.W., unpublished data). Similarly, human thymus also contains pDCs and two subsets of mature CD11c+ cDC: CD11b CD45ROlo DCs that lack myeloid markers and a minority of CD11b+CD45ROhi DCs expressing many myeloid markers (BendrissVermare et al., 2001; Vandenabeele et al., 2001). Thymic pDCs were shown to produce type I IFN in HIV-1-infected thymus, which exerts antiviral effects (Gurney et al., 2004) and upregulates MHC class I expression on thymocytes (Keir et al., 2002). Whether thymic pDC play a role in the differentiation and/or selection of T cell subsets is unclear. Thymic cDC, although sharing many common features, differ from other peripheral DC subsets in that the majority of thymic cDCs in mouse is derived from an intrathymic precursor, suggesting a nonmigratory behavior (Ardavin et al., 1993; Wu et al., 1995, 1996), and they mostly present self-Ag rather than foreign Ag (Steinman et al., 2003). Thymic cDCs play important roles in the induction of central tolerance through the process of negative selection (Gao et al., 1990; Brocker et al., 1997; Goldschneider Immunity 26, June 2007 ª2007 Elsevier Inc. 745

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Reviews and Cone, 2003; Gallegos and Bevan, 2004; Bonasio et al., 2006) as well as the generation of the naturally occurring CD4+CD25+ regulatory T cells (Watanabe et al., 2005; A. Proietto and L.W., unpublished data). Organ-Specific DC Populations in the Spleen The spleen is a rich source of lymphoid tissue-resident DCs. The DC populations in mouse spleen have been well characterized. Three cDC subsets have been identified in the mouse spleen based on the surface expression of CD8a and CD4, in addition to high levels of CD11c expression on all cDCs. These cDC subsets are CD4 CD8+, CD4 CD8 , and CD4+CD8 (Vremec et al., 2000). The CD4 CD8+ cDCs also express CD205, but not Sirp-a. In contrast, the CD4 CD8 and CD4+CD8 cDCs do not express CD205 , but are Sirp-a+ (Vremec et al., 2000; Lahoud et al., 2006). The CD8 CD205 cDCs are located in the marginal zone, whereas the CD8+CD205+ cDCs are in T cell areas (De Smedt et al., 1996). Marginal-zone DC can rapidly migrate into the T cell zone after LPS stimulation (De Smedt et al., 1996). Cell kinetic study via BrdU administration revealed that the splenic cDCs have a rapid turnover rate, with most of the cDCs turning over within 3 days. This study also revealed that the three cDC subsets represent products of separate developmental lineages rather than different maturation states of one cell lineage (Kamath et al., 2000). A significant number of splenic cDC can be generated in situ by the intrasplenic immediate cDC precursors (Naik et al., 2006; Diao et al., 2006). In addition to the cDCs, pDCs are also found in mouse spleen. They are defined as CD11cintCD45RA+B220+. Similar to the blood pDC, the freshly isolated splenic pDC do not have the phenotypic and functional features of the antigen-presenting cDC, but can assume a cDC morphology and upregulate the cDC markers CD11c and MHC class II after activation with microbial stimuli. They represent the major cell type that produce large amounts of type-1 interferon, a cytokine involved in innate immunity to virus (Siegal et al., 1999; Asselin-Paturel et al., 2001; Nakano et al., 2001; O’Keeffe et al., 2002a; Bjorck, 2001). The most likely origin of pDC in the spleen is the peripheral blood, because cells with the characteristics of pDC can be found in mouse blood, and the intrasplenic DC precursors do not differentiate into pDC (O’Keeffe et al., 2003; Naik et al., 2006). A newly identified DC lineage, namely interferonproducing kill DC (IKDC), has also been found in mouse spleen. These IKDCs have a molecular expression profile of NK cells and DCs with a phenotype CD11c+NK1.1+B220+ (Taieb et al., 2006; Chan et al., 2006). Upon activation by various stimuli, IKDCs can produce large amount of IFN-g and kill typical NK target cells and display some antigen-presenting cell activity (Chan et al., 2006). Like NK cells, the development of IKDC requires Id2, but the major precursor population for IKDC appears to be the Lin Sca-1+c-KithiThy1.1 L-selectin+ lymphoid progenitors (LSP) rather than CLPs (Welner et al., 2007). It is therefore suggested that IKDC may arise 746 Immunity 26, June 2007 ª2007 Elsevier Inc.

from a unique differentiation pathway that diverges early from those responsible for NK, pDC, T, and B cells. The studies of splenic DC populations in human have been hampered by the limited tissue sources. One study reported that human splenic DCs were located in marginal zone, T cell, and B cell areas with a phenotype of CD11c+HLA-DQ+CD1a CD4+CD11bloCD16 CD54+ (McIlroy et al., 2001). However, it is not clear how these DC correlate functionally with mouse splenic DC subsets or with the human blood DC subsets. Organ-Specific DC Populations in Lymph Nodes The DC populations found in mouse LNs are more complex. In addition to the three phenotypically and functionally equivalent cDC populations found in mouse spleen, two additional subpopulations have been described (Henri et al., 2001; Hochrein et al., 2001). These correspond to the mature CD8loCD205int and CD8loCD205hi cDC that migrate from the dermis and epidermis, respectively, to the LNs. Subcutanous LNs contain a higher percentage of the CD8loCD205hi LC-like cells than the mesenteric LNs (Henri et al., 2001). The migratory LC-derived DCs are responsible for carrying antigens picked up from periphery to the draining LNs. Organ-Specific DC Populations in Skin Human CD34+ hemopoietic progenitors differentiate into both LCs and dermal DCs in culture with GM-CSF and TNF-a (Caux et al., 1992). CD34+ progenitors differentiate into common lymphoid progenitors (CLPs) and common myeloid progenitors (CMPs). CMPs appear to differentiate into CLA+ (cutaneous lymphocyte antigen) and CLA populations, which subsequently differentiate into CD11c+CD1a+ and CD11c+CD1a DC, respectively (Strunk et al., 1997). Whereas CD11c+CD1a+ DCs migrate into the skin epidermis and become LCs, CD11c+CD1a DCs migrate into the skin dermis and other tissues and become interstitial DCs (Ito et al., 1999). As described above, TGF-b plays a critical role in LC development as demonstrated by the fact that the in vitro generation of LCs from CD34+ progenitors can be greatly enhanced by TGF-b (Caux et al., 1999), and TGF-b-deficient mice lack LCs (Borkowski et al., 1996, 1997). More recent studies further demonstrated that Flt3+ CMPs as well as monocytes could all give rise to LCs in vivo (Mende et al., 2006; Ginhoux et al., 2006). These studies suggest that both LCs and dermal DCs belong to the myeloid DC lineage. DC Populations in Blood Human DC subsets in the blood are well characterized because of tissue accessibility. Human blood contains two types of DC precursors, monocytes and pDC, which can be induced to differentiate into DCs after ex vivo culture (Grouard et al., 1997; Rissoan et al., 1999; Sallusto and Lanzavecchia, 1994). In addition, human blood contains a subset of immature CD11c+ myeloid DC (O’Doherty et al., 1994). Blood CD11c+ mDC subsets are considered ‘‘naive’’ cells that are migrating from the bone marrow to the peripheral tissue. This assumption is based on their

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Reviews immature phenotype and on the fact that DCs do not recirculate from peripheral tissue to blood, as suggested by mouse studies (Austyn et al., 1988; Kupiec-Weglinski et al., 1988). It is currently believed that blood CD11c+ mDCs locate to the secondary lymphoid organs and peripheral tissues as resting interstitial DCs and that they are related to the in vitro generated monocyte-derived or CD34-derived interstitial DCs (Shortman and Liu, 2002). mDC lineage-CD4+CD11c+ or CD4 CD11c+ cells express CD45RO, myeloid markers, such as CD13 and CD33, and the MHC-like molecule CD1c. These phenotypic markers allow clear distinction of blood mDCs from blood pDCs (which lack CD11c but express CD123 and BDCA2) and can be used to purify the two subsets for in vitro studies (Duramad et al., 2003; Rissoan et al., 1999; Soumelis et al., 2002). Blood pDCs express L-selectin and migrate to the secondary lymphoid organs through the high endothelial venules (Yoneyama et al., 2004). Mouse blood also contains two populations of precursor DCs. Cells with the surface phenotype CD11c+CD11b+CD45RA closely resemble the human immature CD11c+ precursor DCs and rapidly transform into CD8+ cDCs after TNF-a stimulation. A second population of cells with the surface phenotype CD11cloCD11b CD45RAhi closely resemble human pDCs by morphology and function. On stimulation with CpG, these cells make large amounts of type-1 IFNs and rapidly develop into DCs that bear CD8 (O’Keeffe et al., 2003).

Concluding Remarks DCs represent a cell system consisting of several phenotypic and functionally distinct subsets. Although the ultimate origin of all cDCs and pDCs is the BM HSCs, DCs, unlike other hemopoietic cell lineages, can develop through either the myeloid or lymphoid pathways from a Flt3-expressing progenitor (Figure 1). Different transcription factors and cytokines play important roles in controlling the development of different DC populations with distinct functional potentials. Although the intrinsic property of each DC subset may dictate their functional specialty, their final maturation and the functional capacities are also influenced by the tissue environments and the cell types they interacted. A better understanding of the detailed processes governing the development and function of these DC subsets is essential for future application of DCs in immune modulation, vaccine design, and immune therapies.

REFERENCES Akagawa, K.S., Takasuka, N., Nozaki, Y., Komuro, I., Azuma, M., Ueda, M., Naito, M., and Takahashi, K. (1996). Generation of CD1+RelB+ dendritic cells and tartrate-resistant acid phosphatasepositive osteoclast-like multinucleated giant cells from human monocytes. Blood 88, 4029–4039. Allman, D., Dalod, M., Asselin-Paturel, C., Delale, T., Robbins, S.H., Trinchieri, G., Biron, C.A., Kastner, P., and Chan, S. (2006). Ikaros is required for plasmacytoid dendritic cell differentiation. Blood 108, 4025–4034.

Anderson, K.L., Perkin, H., Surh, C.D., Venturini, S., Maki, R.A., and Torbett, B.E. (2000). Transcription factor PU.1 is necessary for development of thymic and myeloid progenitor-derived dendritic cells. J. Immunol. 164, 1855–1861. Apostolou, I., Sarukhan, A., Klein, L., and von Boehmer, H. (2002). Origin of regulatory T cells with known specificity for antigen. Nat. Immunol. 3, 756–763. Ardavin, C., Wu, L., Li, C.L., and Shortman, K. (1993). Thymic dendritic cells and T cells develop simultaneously in the thymus from a common precursor population. Nature 362, 761–763. Asselin-Paturel, C., Boonstra, A., Dalod, M., Durand, I., Yessaad, N., Dezutter-Dambuyant, C., Vicari, A., O’Garra, A., Biron, C., Briere, F., and Trinchieri, G. (2001). Mouse type I IFN-producing cells are immature APCs with plasmacytoid morphology. Nat. Immunol. 2, 1144– 1150. Austyn, J.M., Kupiec-Weglinski, J.W., and Morris, P.J. (1988). Migration patterns of dendritic cells in the mouse. Adv. Exp. Med. Biol. 237, 583–589. Banchereau, J., and Steinman, R.M. (1998). Dendritic cells and the control of immunity. Nature 392, 245–252. Bendriss-Vermare, N., Barthelemy, C., Durand, I., Bruand, C., DezutterDambuyant, C., Moulian, N., Berrih-Aknin, S., Caux, C., Trinchieri, G., and Briere, F. (2001). Human thymus contains IFN-alpha-producing CD11c(-), myeloid CD11c(+), and mature interdigitating dendritic cells. J. Clin. Invest. 107, 835–844. Benlagha, K., Wei, D.G., Veiga, J., Teyton, L., and Bendelac, A. (2005). Characterization of the early stages of thymic NKT cell development. J. Exp. Med. 202, 485–492. Bjorck, P. (2001). Isolation and characterization of plasmacytoid dendritic cells from Flt3 ligand and granulocyte-macrophage colonystimulating factor-treated mice. Blood 98, 3520–3526. Blom, B., Ho, S., Antonenko, S., and Liu, Y.J. (2000). Generation of interferon alpha-producing predendritic cell (Pre-DC)2 from human CD34(+) hematopoietic stem cells. J. Exp. Med. 192, 1785–1796. Bonasio, R., Scimone, M.L., Schaerli, P., Grabie, N., Lichtman, A.H., and von Andrian, U.H. (2006). Clonal deletion of thymocytes by circulating dendritic cells homing to the thymus. Nat. Immunol. 7, 1092– 1100. Borkowski, T.A., Letterio, J.J., Farr, A.G., and Udey, M.C. (1996). A role for endogenous transforming growth factor beta 1 in Langerhans cell biology: the skin of transforming growth factor beta 1 null mice is devoid of epidermal Langerhans cells. J. Exp. Med. 184, 2417–2422. Borkowski, T.A., Letterio, J.J., Mackall, C.L., Saitoh, A., Wang, X.J., Roop, D.R., Gress, R.E., and Udey, M.C. (1997). A role for TGFbeta1 in langerhans cell biology. Further characterization of the epidermal Langerhans cell defect in TGFbeta1 null mice. J. Clin. Invest. 100, 575–581. Brocker, T., Riedinger, M., and Karjalainen, K. (1997). Targeted expression of major histocompatibility complex (MHC) class II molecules demonstrates that dendritic cells can induce negative but not positive selection of thymocytes in vivo. J. Exp. Med. 185, 541–550. Burkly, L., Hession, C., Ogata, L., Reilly, C., Marconi, L.A., Olson, D., Tizard, R., Cate, R., and Lo, D. (1995). Expression of relB is required for the development of thymic medulla and dendritic cells. Nature 373, 531–536. Caux, C., Dezutter-Dambuyant, C., Schmitt, D., and Banchereau, J. (1992). GM-CSF and TNF-alpha cooperate in the generation of dendritic Langerhans cells. Nature 360, 258–261. Caux, C., Vanbervliet, B., Massacrier, C., Dezutter-Dambuyant, C., de Saint-Vis, B., Jacquet, C., Yoneda, K., Imamura, S., Schmitt, D., and Banchereau, J. (1996). CD34+ hematopoietic progenitors from human cord blood differentiate along two independent dendritic cell pathways in response to GM-CSF+TNF alpha. J. Exp. Med. 184, 695–706. Caux, C., Massacrier, C., Dubois, B., Valladeau, J., Dezutter-Dambuyant, C., Durand, I., Schmitt, D., and Saeland, S. (1999). Respective involvement of TGF-beta and IL-4 in the development of Langerhans

Immunity 26, June 2007 ª2007 Elsevier Inc. 747

Immunity

Reviews cells and non-Langerhans dendritic cells from CD34+ progenitors. J. Leukoc. Biol. 66, 781–791. Chan, C.W., Crafton, E., Fan, H.N., Flook, J., Yoshimura, K., Skarica, M., Brockstedt, D., Dubensky, T.W., Stins, M.F., Lanier, L.L., et al. (2006). Interferon-producing killer dendritic cells provide a link between innate and adaptive immunity. Nat. Med. 12, 207–213. Chapuis, F., Rosenzwajg, M., Yagello, M., Ekman, M., Biberfeld, P., and Gluckman, J.C. (1997). Differentiation of human dendritic cells from monocytes in vitro. Eur. J. Immunol. 27, 431–441. Chicha, L., Jarrossay, D., and Manz, M.G. (2004). Clonal type I interferon-producing and dendritic cell precursors are contained in both human lymphoid and myeloid progenitor populations. J. Exp. Med. 200, 1519–1524. Corcoran, L., Ferrero, I., Vremec, D., Lucas, K., Waithman, J., O’Keeffe, M., Wu, L., Wilson, A., and Shortman, K. (2003). The lymphoid past of mouse plasmacytoid cells and thymic dendritic cells. J. Immunol. 170, 4926–4932. D’Amico, A., and Wu, L. (2003). The early progenitors of mouse dendritic cells and plasmacytoid predendritic cells are within the bone marrow hemopoietic precursors expressing Flt3. J. Exp. Med. 198, 293–303. Dakic, A., and Wu, L. (2003). Hemopoietic precursors and development of dendritic cell populations. Leuk. Lymphoma 44, 1469–1475. Dakic, A., Shao, Q.X., D’Amico, A., O’Keeffe, M., Chen, W.F., Shortman, K., and Wu, L. (2004). Development of the dendritic cell system during mouse ontogeny. J. Immunol. 172, 1018–1027. De Smedt, T., Pajak, B., Muraille, E., Lespagnard, L., Heinen, E., De Baetselier, P., Urbain, J., Leo, O., and Moser, M. (1996). Regulation of dendritic cell numbers and maturation by lipopolysaccharide in vivo. J. Exp. Med. 184, 1413–1424. Diao, J., Winter, E., Cantin, C., Chen, W., Xu, L., Kelvin, D., Phillips, J., and Cattral, M.S. (2006). In situ replication of immediate dendritic cell (DC) precursors contributes to conventional DC homeostasis in lymphoid tissue. J. Immunol. 176, 7196–7206. Donskoy, E., and Goldschneider, I. (2003). Two developmentally distinct populations of dendritic cells inhabit the adult mouse thymus: demonstration by differential importation of hematogenous precursors under steady state conditions. J. Immunol. 170, 3514–3521.

Goldschneider, I., and Cone, R.E. (2003). A central role for peripheral dendritic cells in the induction of acquired thymic tolerance. Trends Immunol. 24, 77–81. Grouard, G., Rissoan, M.C., Filgueira, L., Durand, I., Banchereau, J., and Liu, Y.J. (1997). The enigmatic plasmacytoid T cells develop into dendritic cells with interleukin (IL)-3 and CD40-ligand. J. Exp. Med. 185, 1101–1111. Guerriero, A., Langmuir, P.B., Spain, L.M., and Scott, E.W. (2000). PU.1 is required for myeloid-derived but not lymphoid-derived dendritic cells. Blood 95, 879–885. Gurney, K.B., Colantonio, A.D., Blom, B., Spits, H., and Uittenbogaart, C.H. (2004). Endogenous IFN-alpha production by plasmacytoid dendritic cells exerts an antiviral effect on thymic HIV-1 infection. J. Immunol. 173, 7269–7276. Hacker, C., Kirsch, R.D., Ju, X.S., Hieronymus, T., Gust, T.C., Kuhl, C., Jorgas, T., Kurz, S.M., Rose-John, S., Yokota, Y., and Zenke, M. (2003). Transcriptional profiling identifies Id2 function in dendritic cell development. Nat. Immunol. 4, 380–386. Henri, S., Vremec, D., Kamath, A., Waithman, J., Williams, S., Benoist, C., Burnham, K., Saeland, S., Handman, E., and Shortman, K. (2001). The dendritic cell populations of mouse lymph nodes. J. Immunol. 167, 741–748. Hochrein, H., Shortman, K., Vremec, D., Scott, B., Hertzog, P., and O’Keeffe, M. (2001). Differential production of IL-12, IFN-alpha, and IFN-gamma by mouse dendritic cell subsets. J. Immunol. 166, 5448– 5455. Hofman, F.M., Danilovs, J.A., and Taylor, C.R. (1984). HLA-DR (Ia)-positive dendritic-like cells in human fetal nonlymphoid tissues. Transplantation 37, 590–594. Honda, K., Mizutani, T., and Taniguchi, T. (2004). Negative regulation of IFN-alpha/beta signaling by IFN regulatory factor 2 for homeostatic development of dendritic cells. Proc. Natl. Acad. Sci. USA 101, 2416– 2421. Ichikawa, E., Hida, S., Omatsu, Y., Shimoyama, S., Takahara, K., Miyagawa, S., Inaba, K., and Taki, S. (2004). Defective development of splenic and epidermal CD4+ dendritic cells in mice deficient for IFN regulatory factor-2. Proc. Natl. Acad. Sci. USA 101, 3909–3914.

Duramad, O., Fearon, K.L., Chan, J.H., Kanzler, H., Marshall, J.D., Coffman, R.L., and Barrat, F.J. (2003). IL-10 regulates plasmacytoid dendritic cell response to CpG-containing immunostimulatory sequences. Blood 102, 4487–4492.

Inaba, K., Inaba, M., Deguchi, M., Hagi, K., Yasumizu, R., Ikehara, S., Muramatsu, S., and Steinman, R.M. (1993). Granulocytes, macrophages, and dendritic cells arise from a common major histocompatibility complex class II-negative progenitor in mouse bone marrow. Proc. Natl. Acad. Sci. USA 90, 3038–3042.

Fogg, D.K., Sibon, C., Miled, C., Jung, S., Aucouturier, P., Littman, D.R., Cumano, A., and Geissmann, F. (2006). A clonogenic bone marrow progenitor specific for macrophages and dendritic cells. Science 311, 83–87.

Ito, T., Inaba, M., Inaba, K., Toki, J., Sogo, S., Iguchi, T., Adachi, Y., Yamaguchi, K., Amakawa, R., Valladeau, J., et al. (1999). A CD1a+/ CD11c+ subset of human blood dendritic cells is a direct precursor of Langerhans cells. J. Immunol. 163, 1409–1419.

Gallegos, A.M., and Bevan, M.J. (2004). Central tolerance to tissuespecific antigens mediated by direct and indirect antigen presentation. J. Exp. Med. 200, 1039–1049.

Izon, D., Rudd, K., DeMuth, W., Pear, W.S., Clendenin, C., Lindsley, R.C., and Allman, D. (2001). A common pathway for dendritic cell and early B cell development. J. Immunol. 167, 1387–1392.

Gao, E.K., Lo, D., and Sprent, J. (1990). Strong T cell tolerance in parent-F1 bone marrow chimeras prepared with supralethal irradiation. Evidence for clonal deletion and anergy. J. Exp. Med. 171, 1101–1121.

Janossy, G., Bofill, M., Poulter, L.W., Rawlings, E., Burford, G.D., Navarrete, C., Ziegler, A., and Kelemen, E. (1986). Separate ontogeny of two macrophage-like accessory cell populations in the human fetus. J. Immunol. 136, 4354–4361.

Geissmann, F., Prost, C., Monnet, J.P., Dy, M., Brousse, N., and Hermine, O. (1998). Transforming growth factor beta1, in the presence of granulocyte/macrophage colony-stimulating factor and interleukin 4, induces differentiation of human peripheral blood monocytes into dendritic Langerhans cells. J. Exp. Med. 187, 961–966.

Jordan, M.S., Boesteanu, A., Reed, A.J., Petrone, A.L., Holenbeck, A.E., Lerman, M.A., Naji, A., and Caton, A.J. (2001). Thymic selection of CD4+CD25+ regulatory T cells induced by an agonist self-peptide. Nat. Immunol. 2, 301–306.

Gilliet, M., Boonstra, A., Paturel, C., Antonenko, S., Xu, X.L., Trinchieri, G., O’Garra, A., and Liu, Y.J. (2002). The development of murine plasmacytoid dendritic cell precursors is differentially regulated by FLT3ligand and granulocyte/macrophage colony-stimulating factor. J. Exp. Med. 195, 953–958. Ginhoux, F., Tacke, F., Angeli, V., Bogunovic, M., Loubeau, M., Dai, X.M., Stanley, E.R., Randolph, G.J., and Merad, M. (2006). Langerhans cells arise from monocytes in vivo. Nat. Immunol. 7, 265–273.

748 Immunity 26, June 2007 ª2007 Elsevier Inc.

Kamath, A.T., Pooley, J., O’Keeffe, M.A., Vremec, D., Zhan, Y., Lew, A.M., D’Amico, A., Wu, L., Tough, D.F., and Shortman, K. (2000). The development, maturation, and turnover rate of mouse spleen dendritic cell populations. J. Immunol. 165, 6762–6770. Keir, M.E., Stoddart, C.A., Linquist-Stepps, V., Moreno, M.E., and McCune, J.M. (2002). IFN-alpha secretion by type 2 predendritic cells up-regulates MHC class I in the HIV-1-infected thymus. J. Immunol. 168, 325–331.

Immunity

Reviews Kiertscher, S.M., and Roth, M.D. (1996). Human CD14+ leukocytes acquire the phenotype and function of antigen-presenting dendritic cells when cultured in GM-CSF and IL-4. J. Leukoc. Biol. 59, 208–218.

Nichogiannopoulou, A., Trevisan, M., Neben, S., Friedrich, C., and Georgopoulos, K. (1999). Defects in hemopoietic stem cell activity in Ikaros mutant mice. J. Exp. Med. 190, 1201–1214.

Kobayashi, T., Walsh, P.T., Walsh, M.C., Speirs, K.M., Chiffoleau, E., King, C.G., Hancock, W.W., Caamano, J.H., Hunter, C.A., Scott, P., et al. (2003). TRAF6 is a critical factor for dendritic cell maturation and development. Immunity 19, 353–363.

O’Doherty, U., Peng, M., Gezelter, S., Swiggard, W.J., Betjes, M., Bhardwaj, N., and Steinman, R.M. (1994). Human blood contains two subsets of dendritic cells, one immunologically mature and the other immature. Immunology 82, 487–493.

Krug, A., Veeraswamy, R., Pekosz, A., Kanagawa, O., Unanue, E.R., Colonna, M., and Cella, M. (2003). Interferon-producing cells fail to induce proliferation of naive T cells but can promote expansion and T helper 1 differentiation of antigen-experienced unpolarized T cells. J. Exp. Med. 197, 899–906.

O’Keeffe, M., Hochrein, H., Vremec, D., Caminschi, I., Miller, J.L., Anders, E.M., Wu, L., Lahoud, M.H., Henri, S., Scott, B., et al. (2002a). Mouse plasmacytoid cells: long-lived cells, heterogeneous in surface phenotype and function, that differentiate into CD8(+) dendritic cells only after microbial stimulus. J. Exp. Med. 196, 1307–1319.

Kupiec-Weglinski, J.W., Austyn, J.M., and Morris, P.J. (1988). Migration patterns of dendritic cells in the mouse. Traffic from the blood, and T cell-dependent and -independent entry to lymphoid tissues. J. Exp. Med. 167, 632–645.

O’Keeffe, M., Hochrein, H., Vremec, D., Pooley, J., Evans, R., Woulfe, S., and Shortman, K. (2002b). Effects of administration of progenipoietin 1, Flt-3 ligand, granulocyte colony-stimulating factor, and pegylated granulocyte-macrophage colony-stimulating factor on dendritic cell subsets in mice. Blood 99, 2122–2130.

Lahoud, M.H., Proietto, A.I., Gartlan, K.H., Kitsoulis, S., Curtis, J., Wettenhall, J., Sofi, M., Daunt, C., O’Keeffe, M., Caminschi, I., et al. (2006). Signal regulatory protein molecules are differentially expressed by CD8- dendritic cells. J. Immunol. 177, 372–382. Laouar, Y., Welte, T., Fu, X.Y., and Flavell, R.A. (2003). STAT3 is required for Flt3L-dependent dendritic cell differentiation. Immunity 19, 903–912. Liu, K., Waskow, C., Liu, X., Yao, K., Hoh, J., and Nussenzweig, M. (2007). Origin of dendritic cells in peripheral lymphoid organs of mice. Nat. Immunol. 8, 578–583. Manz, M.G., Traver, D., Akashi, K., Merad, M., Miyamoto, T., Engleman, E.G., and Weissman, I.L. (2001a). Dendritic cell development from common myeloid progenitors. Ann. N Y Acad. Sci. 938, 167–173. Manz, M.G., Traver, D., Miyamoto, T., Weissman, I.L., and Akashi, K. (2001b). Dendritic cell potentials of early lymphoid and myeloid progenitors. Blood 97, 3333–3341. Maraskovsky, E., Brasel, K., Teepe, M., Roux, E.R., Lyman, S.D., Shortman, K., and McKenna, H.J. (1996). Dramatic increase in the numbers of functionally mature dendritic cells in Flt3 ligand-treated mice: multiple dendritic cell subpopulations identified. J. Exp. Med. 184, 1953–1962. Martin, P., del Hoyo, G.M., Anjuere, F., Ruiz, S.R., Arias, C.F., Marin, A.R., and Ardavin, C. (2000). Concept of lymphoid versus myeloid dendritic cell lineages revisited: both CD8alpha(-) and CD8alpha(+) dendritic cells are generated from CD4(low) lymphoid-committed precursors. Blood 96, 2511–2519. Martin, P., Del Hoyo, G.M., Anjuere, F., Arias, C.F., Vargas, H.H., Fernandez, L.A., Parrillas, V., and Ardavin, C. (2002). Characterization of a new subpopulation of mouse CD8alpha+ B220+ dendritic cells endowed with type 1 interferon production capacity and tolerogenic potential. Blood 100, 383–390.

O’Keeffe, M., Hochrein, H., Vremec, D., Scott, B., Hertzog, P., Tatarczuch, L., and Shortman, K. (2003). Dendritic cell precursor populations of mouse blood: identification of the murine homologues of human blood plasmacytoid pre-DC2 and CD11c+ DC1 precursors. Blood 101, 1453–1459. Pelayo, R., Hirose, J., Huange, J., Garrett, K.P., Delogu, A., Busslinger, M., and Kincade, P.W. (2005). Derivation of 2 categories of plamacytoid dendritic cells in murine bone marrow. Blood 105, 4407–4415. Pickl, W.F., Majdic, O., Kohl, P., Stockl, J., Riedl, E., Scheinecker, C., Bello-Fernandez, C., and Knapp, W. (1996). Molecular and functional characteristics of dendritic cells generated from highly purified CD14+ peripheral blood monocytes. J. Immunol. 157, 3850–3859. Pulendran, B., Banchereau, J., Maraskovsky, E., and Maliszewski, C. (2001). Modulating the immune response with dendritic cells and their growth factors. Trends Immunol. 22, 41–47. Randolph, G.J., Inaba, K., Robbiani, D.F., Steinman, R.M., and Muller, W.A. (1999). Differentiation of phagocytic monocytes into lymph node dendritic cells in vivo. Immunity 11, 753–761. Rathinam, C., Geffers, R., Yucel, R., Buer, J., Welte, K., Moroy, T., and Klein, C. (2005). The transcriptional repressor Gfi1 controls STAT3dependent dendritic cell development and function. Immunity 22, 717–728. Reid, C.D., Stackpoole, A., Meager, A., and Tikerpae, J. (1992). Interactions of tumor necrosis factor with granulocyte-macrophage colonystimulating factor and other cytokines in the regulation of dendritic cell growth in vitro from early bipotent CD34+ progenitors in human bone marrow. J. Immunol. 149, 2681–2688. Ridge, J.P., Fuchs, E.J., and Matzinger, P. (1996). Neonatal tolerance revisited: turning on newborn T cells with dendritic cells. Science 271, 1723–1726.

McIlroy, D., Troadec, C., Grassi, F., Samri, A., Barrou, B., Autran, B., Debre, P., Feuillard, J., and Hosmalin, A. (2001). Investigation of human spleen dendritic cell phenotype and distribution reveals evidence of in vivo activation in a subset of organ donors. Blood 97, 3470–3477.

Rissoan, M.C., Soumelis, V., Kadowaki, N., Grouard, G., Briere, F., de Waal Malefyt, R., and Liu, Y.J. (1999). Reciprocal control of T helper cell and dendritic cell differentiation. Science 283, 1183–1186.

Mende, I., Karsunky, H., Weissman, I.L., Engleman, E.G., and Merad, M. (2006). Flk2+ myeloid progenitors are the main source of Langerhans cells. Blood 107, 1383–1390.

Romani, N., Gruner, S., Brang, D., Kampgen, E., Lenz, A., Trockenbacher, B., Konwalinka, G., Fritsch, P.O., Steinman, R.M., and Schuler, G. (1994). Proliferating dendritic cell progenitors in human blood. J. Exp. Med. 180, 83–93.

Muthukkumar, S., Goldstein, J., and Stein, K.E. (2000). The ability of B cells and dendritic cells to present antigen increases during ontogeny. J. Immunol. 165, 4803–4813. Naik, S.H., Corcoran, L.M., and Wu, L. (2005). Development of murine plasmacytoid dendritic cell subsets. Immunol. Cell Biol. 83, 563–570. Naik, S.H., Metcalf, D., van Nieuwenhuijze, A., Wicks, I., Wu, L., O’Keeffe, M., and Shortman, K. (2006). Intrasplenic steady-state dendritic cell precursors that are distinct from monocytes. Nat. Immunol. 7, 663–671. Nakano, H., Yanagita, M., and Gunn, M.D. (2001). CD11c(+)B220(+)Gr1(+) cells in mouse lymph nodes and spleen display characteristics of plasmacytoid dendritic cells. J. Exp. Med. 194, 1171–1178.

Sallusto, F., and Lanzavecchia, A. (1994). Efficient presentation of soluble antigen by cultured human dendritic cells is maintained by granulocyte/macrophage colony-stimulating factor plus interleukin 4 and downregulated by tumor necrosis factor alpha. J. Exp. Med. 179, 1109–1118. Schiavoni, G., Mattei, F., Sestili, P., Borghi, P., Venditti, M., Morse, H.C., 3rd, Belardelli, F., and Gabriele, L. (2002). ICSBP is essential for the development of mouse type I interferon-producing cells and for the generation and activation of CD8alpha(+) dendritic cells. J. Exp. Med. 196, 1415–1425. Schiavoni, G., Mattei, F., Borghi, P., Sestili, P., Venditti, M., Morse, H.C., 3rd, Belardelli, F., and Gabriele, L. (2004). ICSBP is critically

Immunity 26, June 2007 ª2007 Elsevier Inc. 749

Immunity

Reviews involved in the normal development and trafficking of Langerhans cells and dermal dendritic cells. Blood 103, 2221–2228. Schotte, R., Nagasawa, M., Weijer, K., Spits, H., and Blom, B. (2004). The ETS transcription factor Spi-B is required for human plasmacytoid dendritic cell development. J. Exp. Med. 200, 1503–1509. Serbina, N.V., Salazar-Mather, T.P., Biron, C.A., Kuziel, W.A., and Pamer, E.G. (2003). TNF/iNOS-producing dendritic cells mediate innate immune defense against bacterial infection. Immunity 19, 59–70. Shigematsu, H., Reizis, B., Iwasaki, H., Mizuno, S., Hu, D., Traver, D., Leder, P., Sakaguchi, N., and Akashi, K. (2004). Plasmacytoid dendritic cells activate lymphoid-specific genetic programs irrepective of thr cellular origin. Immunity 21, 43–53. Shortman, K., and Liu, Y.J. (2002). Mouse and human dendritic cell subtypes. Nat. Rev. Immunol. 2, 151–161. Shortman, K., and Naik, S.H. (2007). Steady-state and inflammatory dendritic-cell development. Nat. Rev. Immunol. 7, 19–30. Siegal, F.P., Kadowaki, N., Shodell, M., Fitzgerald-Bocarsly, P.A., Shah, K., Ho, S., Antonenko, S., and Liu, Y.J. (1999). The nature of the principal type 1 interferon-producing cells in human blood. Science 284, 1835–1837. Soumelis, V., Reche, P.A., Kanzler, H., Yuan, W., Edward, G., Homey, B., Gilliet, M., Ho, S., Antonenko, S., Lauerma, A., et al. (2002). Human epithelial cells trigger dendritic cell mediated allergic inflammation by producing TSLP. Nat. Immunol. 3, 673–680. Spits, H., Couwenberg, F., Bakker, A.Q., Weijer, K., and Uittenbogaart, C.H. (2000). Id2 and Id3 inhibit development of CD34(+) stem cells into predendritic cell (pre-DC)2 but not into pre-DC1. Evidence for a lymphoid origin of pre-DC2. J. Exp. Med. 192, 1775–1784. Steinman, R.M., Hawiger, D., and Nussenzweig, M.C. (2003). Tolerogenic dendritic cells. Annu. Rev. Immunol. 21, 685–711. Strunk, D., Egger, C., Leitner, G., Hanau, D., and Stingl, G. (1997). A skin homing molecule defines the langerhans cell progenitor in human peripheral blood. J. Exp. Med. 185, 1131–1136. Sun, C.M., Fiette, L., Tanguy, M., Leclerc, C., and Lo-Man, R. (2003). Ontogeny and innate properties of neonatal dendritic cells. Blood 102, 585–591. Suzuki, S., Honma, K., Matsuyama, T., Suzuki, K., Toriyama, K., Akitoyo, I., Yamamoto, K., Suematsu, T., Nakamura, M., Yui, K., and Kumatori, A. (2004). Critical roles of interferon regulatory factor 4 in CD11bhighCD8alpha- dendritic cell development. Proc. Natl. Acad. Sci. USA 101, 8981–8986. Szabolcs, P., Avigan, D., Gezelter, S., Ciocon, D.H., Moore, M.A., Steinman, R.M., and Young, J.W. (1996). Dendritic cells and macrophages can mature independently from a human bone marrowderived, post-colony-forming unit intermediate. Blood 87, 4520–4530. Tacke, F., and Randolph, G.J. (2006). Migratory fate and differentiation of blood monocyte subsets. Immunobiology 211, 609–618. Taieb, J., Chaput, N., Menard, C., Apetoh, L., Ullrich, E., Bonmort, M., Pequignot, M., Casares, N., Terme, M., Flament, C., et al. (2006). A novel dendritic cell subset involved in tumor immunosurveillance. Nat. Med. 12, 214–219. Tamura, T., Tailor, P., Yamaoka, K., Kong, H.J., Tsujimura, H., O’Shea, J.J., Singh, H., and Ozato, K. (2005). IFN regulatory factor-4 and -8 govern dendritic cell subset development and their functional diversity. J. Immunol. 174, 2573–2581. Tilloy, F., Di Santo, J.P., Bendelac, A., and Lantz, O. (1999). Thymic dependence of invariant V alpha 14+ natural killer-T cell development. Eur. J. Immunol. 29, 3313–3318. Traver, D., Akashi, K., Manz, M., Merad, M., Miyamoto, T., Engleman, E.G., and Weissman, I.L. (2000). Development of CD8alpha-positive dendritic cells from a common myeloid progenitor. Science 290, 2152–2154.

750 Immunity 26, June 2007 ª2007 Elsevier Inc.

Treiner, E., Duban, L., Bahram, S., Radosavljevic, M., Wanner, V., Tilloy, F., Affaticati, P., Gilfillan, S., and Lantz, O. (2003). Selection of evolutionarily conserved mucosal-associated invariant T cells by MR1. Nature 422, 164–169. Vandenabeele, S., Hochrein, H., Mavaddat, N., Winkel, K., and Shortman, K. (2001). Human thymus contains 2 distinct dendritic cell populations. Blood 97, 1733–1741. Vollstedt, S., Franchini, M., Hefti, H.P., Odermatt, B., O’Keeffe, M., Alber, G., Glanzmann, B., Riesen, M., Ackermann, M., and Suter, M. (2003). Flt3 ligand-treated neonatal mice have increased innate immunity against intracellular pathogens and efficiently control virus infections. J. Exp. Med. 197, 575–584. Vremec, D., Zorbas, M., Scollay, R., Saunders, D.J., Ardavin, C.F., Wu, L., and Shortman, K. (1992). The surface phenotype of dendritic cells purified from mouse thymus and spleen: investigation of the CD8 expression by a subpopulation of dendritic cells. J. Exp. Med. 176, 47–58. Vremec, D., Pooley, J., Hochrein, H., Wu, L., and Shortman, K. (2000). CD4 and CD8 expression by dendritic cell subtypes in mouse thymus and spleen. J. Immunol. 164, 2978–2986. Watanabe, N., Wang, Y.H., Lee, H.K., Ito, T., Cao, W., and Liu, Y.J. (2005). Hassall’s corpuscles instruct dendritic cells to induce CD4+CD25+ regulatory T cells in human thymus. Nature 436, 1181– 1185. Weih, F., Carrasco, D., Durham, S.K., Barton, D.S., Rizzo, C.A., Ryseck, R.P., Lira, S.A., and Bravo, R. (1995). Multiorgan inflammation and hematopoietic abnormalities in mice with a targeted disruption of RelB, a member of the NF-kappa B/Rel family. Cell 80, 331–340. Welner, R.S., Pelayo, R., Garrett, K.P., Chen, X., Perry, S.S., Sun, X.H., Kee, B.L., and Kincade, P.W. (2007). Interferon-producing killer dendritic cells (IKDC) arise via a unique differentiation pathway from primitive c-kitHiCD62L+ lymphoid progenitors. Blood 109, 4825–4931. Wu, L., Vremec, D., Ardavin, C., Winkel, K., Suss, G., Georgiou, H., Maraskovsky, E., Cook, W., and Shortman, K. (1995). Mouse thymus dendritic cells: kinetics of development and changes in surface markers during maturation. Eur. J. Immunol. 25, 418–425. Wu, L., Li, C.L., and Shortman, K. (1996). Thymic dendritic cell precursors: relationship to the T lymphocyte lineage and phenotype of the dendritic cell progeny. J. Exp. Med. 184, 903–911. Wu, L., Nichogiannopoulou, A., Shortman, K., and Georgopoulos, K. (1997). Cell-autonomous defects in dendritic cell populations of Ikaros mutant mice point to a developmental relationship with the lymphoid lineage. Immunity 7, 483–492. Wu, L., D’Amico, A., Winkel, K.D., Suter, M., Lo, D., and Shortman, K. (1998). RelB is essential for the development of myeloid-related CD8alpha- dendritic cells but not of lymphoid-related CD8alpha+ dendritic cells. Immunity 9, 839–847. Wu, L., D’Amico, A., Hochrein, H., O’Keeffe, M., Shortman, K., and Lucas, K. (2001). Development of thymic and splenic dendritic cell populations from different hemopoietic precursors. Blood 98, 3376– 3382. Yoneyama, H., Matsuno, K., Zhang, Y., Nishiwaki, T., Kitabatake, M., Ueha, S., Narumi, S., Morikawa, S., Ezaki, T., Lu, B., et al. (2004). Evidence for recruitment of plasmacytoid dendritic cell precursors to inflamed lymph nodes through high endothelial venules. Int. Immunol. 16, 915–928. Zenke, M., and Hieronymus, T. (2006). Towards an understanding of the transcription factor network of dendritic cell development. Trends Immunol. 27, 140–145. Zhou, L.J., and Tedder, T.F. (1996). CD14+ blood monocytes can differentiate into functionally mature CD83+ dendritic cells. Proc. Natl. Acad. Sci. USA 93, 2588–2592.