Cellular Immunology 291 (2014) 3–10

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Review

Aligning bona fide dendritic cell populations across species Charles-Antoine Dutertre a,b, Lin-Fa Wang b,c, Florent Ginhoux a,⇑ a Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A⁄STAR), 8A Biomedical Grove, IMMUNOS Building #3-4, BIOPOLIS, 138648 Singapore, Singapore b Program in Emerging Infectious Disease, Duke-NUS Graduate Medical School, 8 College Road, 169857 Singapore, Singapore c Commonwealth Scientific and Industrial Research Organization, Geelong, Victoria, Australia

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Article history: Received 13 August 2014 Accepted 24 August 2014 Available online 4 September 2014 Keywords: Dendritic cells Dendritic cell subsets Cross-species organization Cross-species conservation XCR1 TLR3 CADM1 SIRPa Plasmacytoid DC

a b s t r a c t Dendritic cells (DC) are professional antigen sensing and presenting cells that link innate and adaptive immunity. Consisting of functionally specialized subsets, they form a complex cellular network capable of integrating multiple environmental signals leading to immunity or tolerance. Much of DC research so far has been carried out in mice and increasing efforts are now being devoted to translating the findings into humans and other species. Recent studies have aligned these cellular networks across species at multiple levels from phenotype, gene expression program, ontogeny and functional specializations. In this review, we focus on recent advances in the definition of bona fide DC subsets across species. The understanding of functional similarities and differences of specific DC subsets in different animals not only brings light in the field of DC biology, but also paves the way for the design of future effective therapeutic strategies targeting these cells. Ó 2014 Elsevier Inc. All rights reserved.

1. Introduction Dendritic cells (DC) were originally described as cells with a stellate morphology capable of efficiently activating naïve T cells [1,2]. The DC population can be subdivided at different levels: firstly, based on their ontogeny, and secondly, on their phenotype, gene expression program and specialized function. Several cell types share features of DC and it can be challenging to understand whether they are truly part of the core DC family, or if they are a more distant relative. In terms of ontogeny, bona fide DC develop in the bone marrow (BM) from common DC precursors, dependent on the growth factor fms-like tyrosine kinase 3 ligand (FLT3L) and its receptor FLT3 [3–5]. This population encompasses plasmacytoid DC (pDC) as well as two subsets of conventional DC (cDC). In addition, Langerhans cells, which populate the outer dermal layer of epithelia, were long considered part of the DC family until recent data demonstrating their unique embryonic ontogeny and FLT3independence revealed that they are in fact an unusual type of tissue-resident macrophage that acquire DC-like functions upon maturation [6]. Lastly, the DC population may also include antigen-presenting cells differentiating from monocytes recruited into tissues by microbial and/or inflammatory stimuli [7]. However, ⇑ Corresponding author. E-mail address: fl[email protected] (F. Ginhoux). http://dx.doi.org/10.1016/j.cellimm.2014.08.006 0008-8749/Ó 2014 Elsevier Inc. All rights reserved.

these monocyte-derived DC are again FLT3-independent [8,9], and it remains unclear whether they truly belong to the DC lineage or represent a distinct type of highly plastic cells able to acquire a multitude of functional capabilities, some of which are shared with cDC [10]. The similarities between human and mouse DC subsets (such as pDC and Langerhans cell early identification in both species) initially supported the notion of conserved organization of the DC network in the two species, but understanding the extent of homology has been initially limited by an absence of shared expression of important subset-discriminatory DC markers. For example, the non-classical MHC class I molecules CD1c and CD1a are prototypical human DC subset markers but do not exist in the mouse, and inversely, Siglec-H, which defines mouse pDC, is absent in humans. Even when markers do exist in both species, the expression patterns can be confoundingly disparate: while CD4 is expressed across human DC subsets, it is only present on splenic CD11b+ DC in mice. In the last few years, important progress has been made in the alignment of DC subsets across species, not only in human and mouse, but also in other animals. In this review, we will focus on the FLT3-dependent bona fide DC, which includes the pDC and cDC sub-populations, and discuss the recent advances that have been made in the molecular, phenotypic and functional alignment of DC subsets across various species. We will incorporate findings

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in mice, humans, non-human primates (rhesus macaques), sheep, swine and avians (chickens) in order to construct a framework that aligns DC subsets, underlining the parallel organization of the DC system across vertebrate species. 1.1. XCR1+CADM1+ DC1 and SIRPa+ DC2 conventional DC In mice, cDC were initially defined as CD11chiMHC-II+ cells [11] and were found in lymphoid tissues (LT) and non-lymphoid tissues (NLT), which they can enter either constitutively or upon inflammation [7,12]. cDC found in LT [spleen and lymph nodes (LN)] are also called resident DC. Those found in NLT such as the skin or the gut are called migratory DC as a result of their observed migration from peripheral tissues to LN through the lymphatics. Two LT cDC subsets that express either CD8a or CD4 were first identified in the spleen. Similarly, migratory DC populations are distinguished by mutually-exclusive surface expression of the integrins CD103 (integrin aE) and CD11b (integrin aM), with the recently discovered exception of a DC population in the intestinal lamina propria that

expresses both [13–15]. In humans, cDC also abundantly express CD11c and MHC-II (HLA-DR) and exist as two subsets (often called myeloid DC subsets), the CD1c (BDCA-1)+ cDC and the CD141 (thrombomodulin, BDCA-3)+ cDC [16,17]. Both human cDC subsets express CD4 but not CD8a [16]. Human CD141+ DC and CD1c+ DC, initially identified in the blood, were also subsequently detected in the spleen, tonsils and LNs, as well as in some NLT such as the liver, lung and skin [18–20]. In contrast to mice, they are found in significant proportions in the blood where they are in a rather immature state compared to DC in tissues [21]. Resident and migratory murine cDC were initially thought to be more different from each other than they really are, since markers used to define them differed between these two localizations. However, the advent of multi-parametric flow cytometry and gene expression analyses allowed the demonstration, both in mice and humans, of a homology between subsets of cDC found in LT and NLT [7]. Functional differences between LT and NLT DC subsets have indeed been described in murine studies [22–24], but the extent to which these differences reflect a true distinction between

Fig. 1. Different subsets of dendritic cells shape distinct types of immune responses. This figure depicts the various phenotypes of DC subsets across species, their conserved phenotype and functional properties. LT, lymphoid tissues; NLT, non-lymphoid tissues and Ag, Antigen.

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the cell types as opposed to a high level of functional plasticity, somewhat characteristic of DC, remains to be seen. Genetic and functional studies have revealed that LT CD8a+ and NLT CD103+ DC subsets together, and LT CD4+ and NLT CD11b+ DC subsets combined, constitute two DC lineages respectively, each with characteristic and unique properties despite their different phenotypes. Importantly, the homology between spleen and NLT cDC subsets was also demonstrated using mice lacking transcription factors that control their development. All cDC develop from a common DC precursor (CDP) that gives rise to both plasmacytoid DC and DC precursors, termed pre-DC [7]. Pre-DC seed tissues where they differentiate under the specific control of the Zbtb46 transcription factor [25,26] into all cDC subsets. Mice lacking IRF8 [27], ID2 [28], Batf3 [29] or Nfil3 [30] exhibit profound defects in the development of both LT CD8a+ and NLT CD103+ cDC, whereas the development of LT CD4+ and NLT CD11b+ cDC is controlled by RelB [31], PU.1 [32], RbpJ [33–35] and IRF4 [36,37]. CD8a+ LT and CD103+ NLT cDC are often referred to as CD8a-like cDC, but CD8a is not a universal marker of this subset, and CD103 is also expressed by intestinal CD11b+ cDC [13–15]. The human homologs of murine DC progenitors remain unidentified, although parallels may well exist since the injection of FLT3L into human volunteers substantially increases the numbers of pDC and cDC in blood [38]. Furthermore, BATF3 and IRF4, two transcription factors dictating the development of mouse cDC, are conserved in human cDC [39–43]. Altogether, based on these advances, it was recently proposed to subdivide murine cDC into only two main subtypes: one classical type 1 DC (cDC1) for CD8a+/CD103+ DC, and cDC2 for CD4+/CD11b+ DC [10]. We will therefore use the denomination cDC1 and cDC2 for the murine cells as a point from which to understand the likely homologies with subsets in others species. 1.2. XCR1+CADM1+ cDC1 across species Gene expression analyses combined with the discovery of novel phenotypic markers and the demonstration of functional similarities has so far allowed us not only to define common phenotypic markers of cDC subsets in the different mouse tissues, but also to suggest some homologies between mouse and human DC [18,44– 50]. Firstly, phenotypic similarities between mouse CD8a+ cDC1 and human CD141+ cDC [48–52], indicated that these two subsets were homologous (we will term them both cDC1 from now). Similar to murine cDC1, human CD141+ DC (cDC1) in LT, NLT and blood specifically express XCR1 [45–47,53,54], CADM1 [43,51] and CLEC9A [48–50,52,55]. While informative, it should be noted that CLEC9A may be unreliably expressed, for example in the gut lamina propria [56], and in inflamed or infected tissues, where CLEC9A membrane expression is lost when human cDC1 mature in response to TLR3 triggering [57]. Furthermore, it is also expressed by pDC and on a subset of DC progenitors in mice [58]. On the other hand, XCR1 is emerging as an important cross-species marker of cDC1, since two studies demonstrated that murine cDC1 [54,59], human CD141+ cDC1 [45,46] and sheep CD26+SIRPa DC [46] were the only leukocytes to express XCR1. XCR1 itself is the receptor for XCL1 (lymphotactin), a chemokine produced by CD8+ T cells and NK cells during infectious and inflammatory responses that is involved in DC-mediated cytotoxic immunity [60]. Sheep CD26+ SIRPa XCR1+ DC also have a molecular signature similar to that of human and mouse cDC1, expressing IDO1, CADM1, and the cDC1-specific transcription factors BATF3, ID2 and IRF8 [61]. Of note, in humans, although cDC1 were initially defined as the CD141+ DC sub-population, CD141 might not in fact be the best marker to define these cells as it is also expressed by endothelial cells and by other tissue DC subsets including migratory CD14+ DC in the skin [18,62]. In addition, human CD141+ DC do not

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express CD8a, in contrast to mouse LT cDC1. Thus, the latest data support the view that the traditional DC subset markers CD8a and CD141 are inferior identifiers of cDC1 populations, and are being superseded by XCR1 and CADM1, which can reliably identify cDC1 across several species. Gene expression profiling lends further support to cross-species alignment of DC subsets. A pioneering study revealed strong similarities between the transcriptomes of human CD141+ cDC1 and CD1c+ cDC2 with murine cDC1 and cDC2, respectively [44]. For example, mouse CD8a+ cDC1 and human CD141+ cDC1 both selectively express genes involved in the balance between tolerance and cross-presentation, while mouse CD11b+ cDC2 and human CD1c+ cDC2 both highly expressed genes involved in the MHC-II antigen presentation pathway. There is also functional evidence of at least partial equivalence between cDC1 from different species. In mice, spleen and LN CD8a+ as well as NLT CD103+ cDC1 are the only DC that efficiently cross-present antigen to CD8+ T cells and thus prime cytotoxic T cell responses [29,63–65]. Human CD141+ cDC1 isolated from both blood [20,45,46] and skin [18] were also shown to possess the greatest capacity to cross-present antigens to CD8+ T cells, when compared to the other DC subsets. Interestingly, while human blood CD141+ cDC1 efficiently cross-presented antigen to CD8+ T cells only in the presence of poly I:C (TLR3 agonist), skin CD141+ cDC1 were capable of cross-presenting antigens in the absence of an exogenous maturation signal. This indicates that, in contrast to those found in the skin, blood CD141+ cDC1 are immature, as previously discussed [21]. Interestingly, CLEC9A, CD205, CADM1 and XCR1, the most conserved molecules that are either specifically or strongly expressed by cDC1 across different species, are also mechanistically involved in the antigen cross-presentation process. The lectins CLEC9A and CD205 are both involved in the uptake of antigen derived from apoptotic/necrotic cells and promote the diversion of these antigens towards the cross-presentation pathway [66,67]. Alongside, CADM1 binds to CRTAM expressed on CD8+ T cells and mediates DC:CD8 adhesion [51], while XCR1 promotes the functional interaction of cDC1 with CD8+ T cells that secrete XCL1 [45,46,54]. Another feature shared by mouse [21,68] and sheep [61] cDC1 is the maintenance of an alkaline pH in endosomes and phagosomes following antigen uptake, a phenomenon that is strongly associated with efficient antigen loading onto MHC-I molecules and consequently, to effective antigen cross-presentation. Altogether, in most species studied, cDC1 express high levels of CLEC9A, CD205, CADM1, XCR1 and exhibit limited endosomal acidification: all of which argues in favor of a cross-species specialization of cDC1 in cross-presentation of antigens derived from apoptotic and/or dead cells. This process is especially relevant for the generation of protective CTL responses against tumors and viruses that infect cells other than DC. Another major phenotypic and functional similarity between mouse and human cDC1 is their strong expression of TLR3 and responsiveness to its ligation [29,69–71]. The natural ligand of TLR3 is viral double-stranded RNA (dsRNA), and it also recognizes synthetic (poly I:C). Similar to mouse CD8a+ splenic cDC1, human blood and liver CD141+ cDC1 produce high levels of IFN-k (also termed IL-28/29 or type-III IFN) upon exposure to poly I:C [71] and viruses such as herpes simplex virus-1 (HSV-1), parapoxvirus or hepatitis C virus [71–73]. Functionally, type-III IFN are similar to type-I IFN and possess antiviral, antitumor and immune-modulating functions [71,74]. Very recently, DC sharing phenotypic, molecular and functional similarities to mouse, human and sheep cDC1 were defined in other species including macaques, pigs and chickens [75,76]. In pig and macaques, cDC1 were the only cells to strongly express CADM1. In macaques, cDC1 were also XCR1 positive and expressed CLEC9A and BATF3 at the RNA level; similar to human cDC1, they also strongly expressed CD205 and CD162 and were responsive to

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TLR3 triggering [75,76]. cDC that closely resemble cDC1 in terms of FLT3, CADM1, CD205, TLR3 and XCR1 expression, were also identified for the first time in a non-mammalian species, the chicken [77]. These recent studies confirmed that BATF3, XCR1, CADM1, TLR3 and, to a lesser extent, CLEC9A are conserved markers of cDC1 across species. CLEC9A was detected only at the RNA level both in macaque [75] and sheep [77], but surface protein expression was only detectable on CADM1+XCR1+ cDC1 in 2 of the 27 macaques tested [75]. Among leukocytes, cDC1 also have the highest expression level of other molecules including CD205 (DEC-205) in mouse, human, macaque and sheep [61,75,78], CD162 in human and macaque [51,75], and CD26 in mouse, human and sheep [46,61,79]. Although some specialized functions, such as secretion of IFN-k, are perfectly conserved between cDC1 of various species [71], the superiority of cDC1 in terms of antigen cross-presentation and IL-12p70 production has been suggested to be less important in humans compared to mice [80,81]. However, practical constraints mean that these functions have so far been studied using bloodderived human DC that are neither functionally mature nor necessarily representative of their in vivo tissue counterparts [18]. The conclusion remains unclear, but the identification of XCR1+ CADM1+ cDC1 in non-human primates, which are the closest animal model to humans, should finally allow the accurate evaluation of these specialized functions in vivo. Further advances may also be made as reagent availability is improving: as noted, XCR1 and CADM1 are now commonly accepted as a common marker of cDC1 across species, and while no commercially available reagent to detect XCR1 by flow cytometry is available, the anti-CADM1 (SynCam, Necl2) monoclonal antibody (clone 3E1), which specifically binds to the CADM1 molecule in mouse, human, macaque, sheep and pig, will likely allow the delineation of cDC1 in other mammalian species in the future.

1.3. SIRPa+ cDC2 across species The understanding of murine LT and NLT cDC2 and the alignment of cDC2 across species have not reached the same level as for cDC1. In part, this may be attributed to the substantial phenotypic overlap between CD11b+ cDC2 and other cells, such as tissue-resident macrophages and monocyte-derived DC, which has hindered their analysis in mice [7,40,42,82,83]. Contrary to cDC2, monocyte-derived DC and macrophages develop and are maintained independently of FLT3L, a distinction that allowed more precise delineation of CD11b+ cDC2 as SIRPa+CD11b+Ly6C CD64 MerTK cells [40,53,83–85]. Furthermore, high expression of ESAM (endothelial cell-specific adhesion molecule) characterizes murine spleen CD4+ cDC2 [34]. Human CD1c+ cDC have a gene signature resembling that of mouse cDC2 [44] and strongly express CD11c, CD11b and SIRPa, as do murine cDC2 [16,19,40,56,86]. Interestingly, in sheep lymph, skin and skin-draining lymph nodes, cells expressing the non-classical MHC class I molecule CD1b comprise two subsets based on the expression of CD26 and SIRPa, CD26+SIRPa cDC1 (described above) and a CD26 SIRPa+ subset, whose gene expression profile and phenotype overlap with both human and mouse cDC2 [46,61]. Contrary to mouse and humans, sheep cDC2 do not express CD11b. Similarly, MHC-II+FLT3+SIRPa+ CD16 cells that do not express CADM1 or CLEC9A were detected in the lymph and skin of pigs and could correspond to a cDC2 population [76], while the major subset of DC in the lymph of bovines defined by their expression of SIRPa and CD205 could also correspond to cDC2 [87,88]. A recent study in mice has also confirmed that the cDC2 marker that best distinguishes these cells from XCR1+ cDC1 in gut lymphoid and non-lymphoid tissues is SIRPa [56]. Therefore, in most mammalian species studied, SIRPa

represents the only conserved phenotypic marker to define cDC2 and should be used in the future to characterize this subset. In macaques, particularly in the context of SIV infection, cDC have been defined as CD3/CD14/CD20/CD123 MHC-II+CD11c+ cells, which may also express CD16 and low levels of CD11b [89– 91]. Intriguingly, these CD11c+ cells only express an intermediate level of MHC-II, whereas most CD11c cells among lin CD123 cells exhibited strong MHC-II expression levels but were not considered as cDC [89]. However, recent studies have now revised this belief and shown that macaque cDC2 are MHC-IIhiCD1c+, but CD11clo/ [75,92]. Blood and spleen MHC-IIintCD11chi cells, previously defined as cDC, are in fact CD14+/ CD16++ non-classical monocytes that strongly express CD11c [75], as do their counterparts in humans [93]. SIRPa expression in these populations remains to be tested. Functionally, mouse, human and chicken cDC2 are potent inducers of CD4+ T cell proliferation [40,77,94] as well as polarization towards Th2 and Th17 responses. For example, murine lung CD11b+ cDC2 are the primary drivers of Th2 responses following exposure to house dust mite allergens [82,95], and of Th17 immunity, through release of IL-23, both in the steady state and during Aspergillus fumigatus infection [40]. A subset of mouse CD11b+ cDC2 also expresses CD103; these cells, which are unique to the intestine, produce the Th17-inducing cytokines IL-6 and IL-23 in steady state or following Citrobacter rodentium infection or following immunization with a TLR5 ligand [40,42,96], and also migrate to LNs where they induce Th1/17 (IL-17+IFNc+) CD4+ T cells. Similarly, human CD1c+ cDC2 in the skin can produce IL-23 [18,97], and in the lung, potently induce Th17 cells upon Aspergillus fumigatus challenge [40]. In conclusion, across species, cDC1 are best defined as XCR1+ CADM1+ and are endowed both with cross-presentation capacity and the ability to secrete IFN-k following TLR3 triggering. Overall, cDC1 seem to be tailored towards defense against intracellular pathogens (Fig. 1). Alongside, cDC2 are MHC-IIhiSIRPa+ and efficiently present antigens to CD4+ T cells, favoring their polarization into Th2 and Th17 cells. Collectively, cDC2 have the complementary specialization for detection and presentation of antigens derived from extracellular pathogens, initiating appropriate (or perhaps inappropriate, in the case of allergy) T cell responses (Fig. 1). 1.4. Plasmacytoid DC (pDC) across species While the establishment of a clear homology between cDC subsets across species has emerged only recently, pDC have been extensively characterized in multiple mammalian species, at least functionally. Across species, pDC specialize in type-I interferon (IFNa and IFNb) secretion following interaction with viruses, and their only known specific and conserved markers are the transcription factor E2-2 and TLR7. pDC, which abundantly express TLR7 and TLR9 [44,98], were initially called natural interferon-producing cells since they are mostly responsible for type-I interferon production upon stimulation with viruses in humans [99–101], mice [102–104], macaques [105], sheep and pigs [106,107]. Furthermore, mouse and human pDC also secrete IFN-k in response to parapoxviruses or herpes simplex virus-1 [71]. There are additional similarities in terms of development. It has recently been shown that mouse pDC are regulated by the transcription factor E2-2 (Tcf4), which counteracts the action of Id2 required for cDC1 development, and that it is also specifically expressed in human and sheep pDC [107–109]. Although pDC functionality, and likely their development, is strongly conserved across species, phenotypic parallels are less obvious (Fig. 1). Mouse pDC are LinnegMHC-II+ and specifically

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express B220 (CD45R), CD317 (BST2) and SiglecH, while human and macaque pDC express IL-3Ra (CD123), CD303 (BDCA-2) and CD304 (BDCA-4) [86,92,105,110]. Human pDC also express BST2, but so do cDC, and SiglecH has no counterpart in human [44,98]. Contrary to human and mouse, macaque and sheep pDC only weakly express MHC-II [75,106,111]. In sheep, pDC were identified as CD11c CD45RB+ cells exhibiting a plasmacytoid morphology, expressing high levels of TLR7, TLR9 and IFN regulatory factor 7 (IRF7), and producing type-I IFN following TLR9 triggering [106,107]. In pigs, pDC are defined as MHC-II+CD14 CD4hiSIRPalo and like their other mammalian homologs, they are the major source of type-I IFN following TLR7 and TLR9 triggering [112–114]. 2. Conclusion In the last few years, major steps forward have been made in the alignment of DC subsets across species, not only in human and mouse, but in non-human primate, ovine, swine and bird species. The identification of homologous DC subsets with conserved functions supports the notion of parallel organization of the DC network in all these species and highlights their functional importance. Among all bona fide DC, the cDC1 subset is the one that displays the greatest conservation, in terms of phenotype (XCR1+CADM1+TLR3+CLE9A+), gene expression profile, expression of specific transcription factors (IRF8, BATF3), and functional specializations including antigen cross-presentation, Th1 polarization and IFN-k secretion in response to TLR3 triggering. Their molecular signature and unique functions underline their crucial role against intracellular pathogens. As compared to cDC1, cDC2 display a less conserved phenotype across species, although expression of SIRPa is emerging as a potential cDC2 specific marker that transcends species barriers. Nevertheless, cDC2 cells are specialized in antigen presentation to CD4+ T cells and polarization towards Th2 or Th17 responses under certain conditions, underlining their important role against extracellular pathogens. Finally, although pDC do not have conserved phenotypic markers across species, they have always traditionally been defined by their major function, i.e., type-I IFN secretion in response to viral stimuli, highlighting their indispensable role during viral infections. Importantly, although most specialized functions of DC subsets are conserved between species, some of them are not such as the strong IL-12p70 production capacity of mouse cDC1, which is not seen in human cDC1. These differences are most probably linked to species-specific adaptation to the environment, for example the different pathogens encountered by each. Therefore, as recently proposed by Guilliams and colleagues [10], since the expression of transcription factors required for their development (BATF3 and IRF8 for cDC1, IRF4 for cDC2 and E2-2 for pDC) is highly conserved across species, a common nomenclature to define DC subsets across species should rely primarily on their ontogeny and the expression of specific transcription factors required for their development, and only secondarily on their location, function and phenotype. The process of accurate cross-species alignment of DC subsets will facilitate the investigation of DC subsets in species relevant for human health. For example, while DC have never been described in bats, these animals are one of the most important reservoirs for many zoonotic viruses (SARS, Ebola, Marburg, Nipah, and Hendra viruses). While these infections are often lethal to both humans and livestock, they are frequently asymptomatic in bats [59,115,116]. Understanding bat DC subsets, and defining bat-specific molecular and functional properties should allow us to determine why these deadly viruses do not cause clinical disease in these animals. Accordingly, we have begun to study pDC and cDC subsets in the black flying fox (Pteropus alecto), a representative mega bat from the suborder Yinpterochiroptera and found

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evidence of a similar network to that found in humans and mice (Dutertre, Wang and Ginhoux, unpublished results). Unraveling the specialized conserved functions of DC subsets will facilitate the translation of knowledge from mouse into human and other species. This will allow us to manipulate the DC compartment for therapeutic benefit, and to design new therapeutic strategies to target specific DC subsets for both human and veterinary applications. Acknowledgments The studies conducted in the authors’ groups are funded in part by the Singapore Immunology Network (SIgN) core budget and the Competitive Research Programme Grant (NRF-CRP10-2012-05) from the National Research Foundation Singapore. We would also like to thank Dr Lucy Robinson of Insight Editing London for her assistance in manuscript preparation. References [1] R.M. Steinman, Z.A. Cohn, Identification of a novel cell type in peripheral lymphoid organs of mice. I. morphology, quantitation, tissue distribution, J. Exp. Med. 137 (1973) 1142–1162. [2] R.M. Steinman, M.D. Witmer, Lymphoid dendritic cells are potent stimulators of the primary mixed leukocyte reaction in mice, Proc. Natl. Acad. Sci. U.S.A. 75 (1978) 5132–5136. [3] F. Ginhoux, K. Liu, J. Helft, M. Bogunovic, M. Greter, D. Hashimoto, J. Price, N. Yin, J. Bromberg, S.A. Lira, E.R. Stanley, M. Nussenzweig, M. Merad, The origin and development of nonlymphoid tissue CD103+ DCs, J. Exp. Med. 206 (2009) 3115–3130. [4] H.J. McKenna, K.L. Stocking, R.E. Miller, K. Brasel, T. De Smedt, E. Maraskovsky, C.R. Maliszewski, D.H. Lynch, J. Smith, B. Pulendran, E.R. Roux, M. Teepe, S.D. Lyman, J.J. Peschon, Mice lacking flt3 ligand have deficient hematopoiesis affecting hematopoietic progenitor cells, dendritic cells, and natural killer cells, Blood 95 (2000) 3489–3497. [5] C. Waskow, K. Liu, G. Darrasse-Jeze, P. Guermonprez, F. Ginhoux, M. Merad, T. Shengelia, K. Yao, M. Nussenzweig, The receptor tyrosine kinase Flt3 is required for dendritic cell development in peripheral lymphoid tissues, Nat. Immunol. 9 (2008) 676–683. [6] F. Ginhoux, M. Merad, Ontogeny and homeostasis of Langerhans cells, Immunol. Cell Biol. 88 (2010) 387–392. [7] M. Merad, P. Sathe, J. Helft, J. Miller, A. Mortha, The dendritic cell lineage: ontogeny and function of dendritic cells and their subsets in the steady state and the inflamed setting, Annu. Rev. Immunol. 31 (2013) 563–604. [8] C. Auffray, M.H. Sieweke, F. Geissmann, Blood monocytes: development, heterogeneity, and relationship with dendritic cells, Annu. Rev. Immunol. 27 (2009) 669–692. [9] D. Kingston, M.A. Schmid, N. Onai, A. Obata-Onai, D. Baumjohann, M.G. Manz, The concerted action of GM-CSF and Flt3-ligand on in vivo dendritic cell homeostasis, Blood 114 (2009) 835–843. [10] M. Guilliams, F. Ginhoux, C. Jakubzick, S.H. Naik, N. Onai, B.U. Schraml, E. Segura, R. Tussiwand, S. Yona, Dendritic cells, monocytes and macrophages: a unified nomenclature based on ontogeny, Nat. Rev. Immunol. 40 (2014) 571– 578. [11] J.P. Metlay, M.D. Witmer-Pack, R. Agger, M.T. Crowley, D. Lawless, R.M. Steinman, The distinct leukocyte integrins of mouse spleen dendritic cells as identified with new hamster monoclonal antibodies, J. Exp. Med. 171 (1990) 1753–1771. [12] M. Guilliams, S. Henri, S. Tamoutounour, L. Ardouin, I. Schwartz-Cornil, M. Dalod, B. Malissen, From skin dendritic cells to a simplified classification of human and mouse dendritic cell subsets, Eur. J. Immunol. 40 (2010) 2089– 2094. [13] C. Varol, A. Vallon-Eberhard, E. Elinav, T. Aychek, Y. Shapira, H. Luche, H.J. Fehling, W.D. Hardt, G. Shakhar, S. Jung, Intestinal lamina propria dendritic cell subsets have different origin and functions, Immunity 31 (2009) 502– 512. [14] M. Bogunovic, F. Ginhoux, J. Helft, L. Shang, D. Hashimoto, M. Greter, K. Liu, C. Jakubzick, M.A. Ingersoll, M. Leboeuf, E.R. Stanley, M. Nussenzweig, S.A. Lira, G.J. Randolph, M. Merad, Origin of the lamina propria dendritic cell network, Immunity 31 (2009) 513–525. [15] M. Bogunovic, A. Mortha, P.A. Muller, M. Merad, Mononuclear phagocyte diversity in the intestine, Immunol. Res. 54 (2012) 37–49. [16] K.P. MacDonald, D.J. Munster, G.J. Clark, A. Dzionek, J. Schmitz, D.N. Hart, Characterization of human blood dendritic cell subsets, Blood 100 (2002) 4512–4520. [17] L. Ziegler-Heitbrock, P. Ancuta, S. Crowe, M. Dalod, V. Grau, D.N. Hart, P.J. Leenen, Y.J. Liu, G. MacPherson, G.J. Randolph, J. Scherberich, J. Schmitz, K. Shortman, S. Sozzani, H. Strobl, M. Zembala, J.M. Austyn, M.B. Lutz, Nomenclature of monocytes and dendritic cells in blood, Blood 116 (2010) e74–e80.

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