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as APC and the Dendritic Cell Myth David A. Hume This information is current as J Immunol 2008; 181:5829-5835; ; of September 28, 2021. doi: 10.4049/jimmunol.181.9.5829 http://www.jimmunol.org/content/181/9/5829 Downloaded from References This article cites 99 articles, 42 of which you can access for free at: http://www.jimmunol.org/content/181/9/5829.full#ref-list-1

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The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2008 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Macrophages as APC and the Dendritic Cell Myth David A. Hume1

Dendritic cells have been considered an immune cell The mononuclear system (MPS) is a family of cells type that is specialized for the presentation of Ag to that comprises committed precursors in the , cir- naive T cells. Considerable effort has been applied to culating , and tissue macrophages in every or- separate their lineage, pathways of differentiation, and gan in the body (9). Many subpopulations of macrophages have effectiveness in Ag presentation from those of macro- been defined based upon surface markers (10, 11). In this re- phages. This review summarizes evidence that dendritic view, I will examine the evidence that DC are a part of the MPS cells are a part of the mononuclear phagocyte system and and will argue that there are no pathways of development, markers, or even functions in Ag presentation that distinguish are derived from a common precursor, responsive to the them from macrophages. Downloaded from same growth factors (including CSF-1), express the same surface markers (including CD11c), and have no Differentiation in the mononuclear phagocyte system unique adaptation for Ag presentation that is not shared The definition of the MPS was originally intended to separate by other macrophages. The Journal of Immunology, cells of this family from lymphoid cells (T and B ), 2008, 181: 5829–5835. (which are polymorphonuclear rather than mono- http://www.jimmunol.org/ nuclear), and endothelial cells (which had previously been he early 1970s were among the most exciting periods in grouped together with macrophages under the definition of the the history of cellular immunology, with the recogni- reticuloendothelial system). Each of these separations has been T tion that T activation requires the process- challenged by subsequent observations: the progenitor cells in- ing of Ag into peptides that are presented in the context of self filtrating the retain myeloid potential; fetal liver can give rise to mixed colonies of macrophages and B cells during class I or class II major histocompatibility molecules. Several fetal development; -like cells derived from the yolk groups recognized that presentation of exogenous Ags was a sac proliferate extensively without going through an obvious specialized function of adherent cells. A novel cell population of by guest on September 28, 2021 stage; and granulocytes can be transformed into mac- cells in the and lymph nodes appeared to be adapted to rophages and monocytes into endothelial cells (9, 12, 13). Most the process of Ag presentation. These cells, dubbed “dendritic 2 tissues contain substantial macrophage populations, up to 15% cells” (DC) were nonphagocytic cells considered to be quite of total cells, that share a “dendritic” morphology, defined cel- distinct from “macrophages” (1–3). Evolution of the DC con- lular location, and expression of surface markers and gene ex- cept required the recognition that “immature DC” internalize pression profiles (9, 12). Fig. 1A shows an example of F4/80 and store Ag and subsequently mature into effective APC. Rec- staining of mouse intestinal lamina propria. Note the way that ognition of different forms of activation (Th1, Th2, F4/80-positive cells spread along the basal lamina of the epithe- Th17, Treg) necessitated the definition of DC subsets special- lium. This location is typical of macrophages associated with ized to activate T cell subsets (3–6). Because Ag presentation simple epithelia throughout the body; a particularly striking ex- per se could not easily be viewed in vivo, surface markers were ample is shown in Fig. 1B in the renal medulla and many more used as surrogates to identify DC. Among these markers, in the images can be viewed at www.macrophages.com. We have re- mouse the expression of the integrin CD11c (CR4, Itgax; cently generated transgenic animals (MacGreen mice) in which p150,95) on the cell surface (7) or that of a CD11c reporter all of these cells express enhanced GFP (EGFP) by using the transgene (8) has become a de facto definition of DC that dis- promoter of the csf1r gene (14). Fig. 1C shows a comparable tinguishes them from macrophages. The use of such markers, as view to Fig. 1A of the gut with this transgene, and Fig. 1D, well as the discovery of culture systems that drive the produc- displays a view of the showing the remarkable frequency of tion of relatively pure populations of DC, led many to talk of a myeloid cells in this organ. Macrophages also line the entire mi- DC lineage or indeed multiple DC lineages (4, 5). crovasculature, in this instance spreading longitudinally along

The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edin- 2 Abbreviations used in this paper: DC, dendritic cell; DTR, diphtheria toxin receptor; burgh, Scotland, United Kingdom EGFP, enhanced GFP; Flt3L, Fms-like tyrosine kinase 3 ligand; MDP, macrophage-DC progenitor; MPS, mononuclear phagocyte system. Received for publication June 25, 2008. Accepted for publication August 18, 2008. The costs of publication of this article were defrayed in part by the payment of page charges. Copyright © 2008 by The American Association of Immunologists, Inc. 0022-1767/08/$2.00 This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 1 Address correspondence and reprint requests to Prof. David Hume, The Roslin In- stitute, Roslin Biocentre, Roslin EH25 9PS, Midlothian, Scotland, U.K. E-mail ad- dress: [email protected] www.jimmunol.org 5830 BRIEF REVIEWS: THE DENDRITIC CELL MYTH

the diversity of tissue and inflammatory macrophages, it is mis- leading to identify a single typical macrophage population as a comparator to a DC in studies of Ag presentation.

CSF and the production of mononuclear Part of the support for DC as a separate cell type from macro- phages has come from efforts to show that different growth fac- tors promote their development. The production of mononu- clear phagocytes from progenitor cells is directed by CSF, including M-CSF (CSF-1), GM-CSF, and Fms-like tyrosine kinase 3 ligand (Flt3L). Deficiency of CSF-1 in the mouse (op/ op) and rat (tl/tl) highlights the importance of tissue macro- phages in many aspects of normal development (21, 22). Ini- FIGURE 1. Upper panels show a section of small intestinal lamina propria tially, analysis of the op/op mutation suggested that CSF-1 was (A) and a section of renal medulla (B) from a perfusion-fixed mouse stained for the macrophage-restricted F4/80 Ag (brown). Note the dendritic morphology not required for DC development, but subsequent knockout of and spreading in the plane of the epithelial basement membranes. Lower panels the CSF-1 receptor gene in the mouse produced a more pene- show sections of small intestine (C) and lung (D) of MacGreen mice in which trant phenotype (23), perhaps due in part to the existence of a Downloaded from the EGFP marker is expressed from the CSF1R promoter region. Based upon second ligand for the CSF-1 receptor IL-34 (24). Both the location, morphology, and numbers, it is difficult to sustain the argument that CSF-1 and the CSF-1R mutations cause significant reductions these macrophage cells are distinct from “DC” identified based upon CD11c or in populations of DC and their presumptive precursors (23, CX3CR1 in these locations (86–89, 94). 25). CSF-1R (and the csf1r transgene) is expressed by all classi- cal and immature DC (25, 26). Injection of CSF-1 into mice the vessel wall. In a movie of the capillaries of the cremaster muscle expanded the circulating CD11b/CD11c-positive mononu- http://www.jimmunol.org/ in MacGreen mice (Ref. 15 and see www.macrophages.com) we clear cells in blood (27) and the splenic population of CD11c- can observe these cells extending processes into the blood flow positive cells as well as plasmacytoid DC (28). As the sole stim- in real time. The ability of vessel-lining macrophages to sample ulus in vitro, CSF-1 promotes the growth of pure cultures of the lumenal contents was first reported in the 1950s (16, 17). A proliferating macrophages from mouse bone marrow; only a special subset of vessel-lining macrophages also extends along subset of the resulting cells generally expresses the Ag-represent- lymphatic vessels (not shown), and recently their importance in ing apparatus, although it can be induced to do so by IFN-␥ Ag capture in the subcapsular sinus of lymph nodes has been (29). These cells resemble more closely the cells that infiltrate recognized (18). sterile inflammatory sites, exemplified by peritoneal exudate by guest on September 28, 2021 The MPS of individual hemopoietic and lymphoid organs is cells elicited by a stimulus such as thioglycollate broth (30, 31). diverse, with several subcompartments and functions (19). In A key discovery in the DC field was the observation that GM- the spleen, for example, there are interdigitating cells of the T CSF (alone or in combination with IL-4) can promote the ex- cell areas (which some would consider the classical DC), vascu- pansion/differentiation of bone marrow and blood monocytes lar-lining macrophages of the red pulp, sinusoidal macrophages into cells with APC potential that can be matured further with of the red pulp in direct contact with the blood (the major func- stimuli such as microbial products (32). This finding has led to tion of which is elimination of effect RBC), marginal zone mac- numerous studies in which GM-CSF-stimulated cells are rophages and metallophils, subcapsular macrophages, imma- equated with DC and are contrasted to CSF-1-stimulated cells ture monocytes derived from hemopoiesis in the red pulp, and (macrophages) in terms of their ability to present Ag. Interest- active tingible body macrophages of germinal centers that elim- ingly, macrophage biology groups have studied GM-CSF-stim- inate dying T and B cells. Each of these subpopulations can be ulated cells as a model of alternative macrophage development distinguished by surface marker expression. So, even in a single (33). Because CSF-1 is present in the circulation and in all tis- organ, resident tissue macrophages can be very heterogeneous. sues in vivo (22) whereas GM-CSF is inducible by stimuli such During development and in sterile wounds or tissue injury the as LPS or T cell mitogens, GM-CSF presumably always acts in resident macrophage is supplemented from the circulation and vivo in the presence of CSF-1. One of the earliest events in the the activities of the inflammatory cells are biased toward phago- response of macrophages to any microbial agonist is the cleav- cytosis, extracellular proteolysis, and the production of growth age of the CSF-1 receptor mediated by a TNF-␣-converting en- factors that promote growth and repair (20). Infectious agents zyme and the consequential regulation of CSF-1-dependent and/or immunological stimuli attract macrophages that differ genes (30, 34). Cells differentiated in GM-CSF express splice greatly depending on the precise nature of the challenge. These variants of the CSF-1 receptor that may encode a soluble decoy phenotypes have been classified into two classes of “activation”: receptor (35, 36). So, both GM-CSF and APC maturation sig- classical activation is directed toward antimicrobial and tumori- nals may act in part by opposing CSF-1 action. The other key cidal effector function with the Th1 product IFN-␥ being the factor to consider is IFN-␥, which is a profound activator of archetypal activating factor, whereas alternative activation, in macrophage cytocidal function and class II MHC expression which the Th2 product IL-4 is implicated, is associated with the and is normally produced alongside GM-CSF by activated T suppression of classical activation and responses to parasites and cells (37). IFN-␥ as a sole stimulus is myelosuppressive and tumors (11). Literally hundreds of surface markers and endo- blocks CSF-1 action; yet, in combination with GM-CSF and cytic receptors display heterogeneous expression on particular CSF-1 it actually promotes mononuclear phagocyte prolifera- resident or activated macrophage populations or subsets. Given tion (38). The Journal of Immunology 5831

Like GM-CSF, Flt3L can expand immature or mature mouse was the visualization of a subset of monocytes that patrol the and human APC populations in bone marrow cultures, al- endothelial surface (55). Some monocyte subsets may already though the phenotypic characteristics may be somewhat dis- have a distinct tendency to acquire APC activity. Jakubzick tinct and, like CSF-1, it can greatly expand the population of et al. (56) claimed that distinct monocyte subsets contribute to CD11c-positive cells in spleen and lymph nodes when injected different DC populations in the lung, distinguished mainly by into mice (39). Knockout of Flt3L causes a significant loss of expression of another integrin, CD103. In the rat, the CD11c-positive cells in spleen and and lung pa- CX3CR1/CD43-high population can give rise to so-called renchyma, although the phenotype is difficult to interpret given veiled cells, the APC of afferent lymph, following transplan- a more global defect in leukocyte cellularity in marrow and tation (57). However, there is no strong evidence to support blood (40, 41). Interestingly, the deficiency in parenchymal the existence of a committed DC-monocyte, and their deri- DC in lung had no impact on lung-associated immune re- vation from monocytes places DC clearly within the defini- sponses (42). tion of the MPS. Macrophage deactivation is a crucial step in the resolution of all inflammatory lesions controlled by “ suppres- sor genes” (43). As a subset of the activation response, APC ac- Macrophages as suppressor cells tivity is also likely to be switched off and be replaced by the Steinman and Witmer (58) argued that purified DC account wound repair macrophage phenotype required for resolution. for all of the stimulatory activity of the spleen in an allogeneic

Human monocyte-derived APC grown in GM-CSF and IL-4 MLR. This conclusion has evolved to a point where DC has Downloaded from retain the ability to reprogram to a macrophage phenotype in become synonymous with APC, and biochemical explanations response to CSF-1 and, vice versa, monocyte-derived macro- for the superior APC activity of DC have been sought. Trom- phages can acquire APC activity (44–47). In the mouse, all tis- betta and Mellman (3) review the pathways for uptake, intra- sue DC express a CSF-1R-EGFP transgene (14, 25), and CSF-1 cellular trafficking, and processing of potential Ags in APC. A treatment of so-called immature DC such as Langerhans cells central theme, based upon the work of Delamarre et al. (59), is can maintain them in the immature state and prevent induction that DC are actively phagocytic but degrade engulfed Ag more http://www.jimmunol.org/ of CD11c, class II MHC, and costimulators (48). slowly and retain it for subsequent presentation to T cells. The In summary, MPS cells are exposed during their differentia- apparent difference between DC and macrophages in Ag-pro- tion and migration to combinations of growth factors such as cessing and presentation may be mouse strain specific. The CSF-1/IL34, GM-CSF, IL-4, IFN-␥, and Flt3L, each of which commonly used mouse strain C57BL/6 has a mutation affect- contribute to their cellular phenotype. Cells grown in any one ing the expression of cathepsin E (60), and a knockout of ca- of these factors on their own probably have no counterpart in thepsin E on the 129/Sv background impairs Ag presentation vivo, and there is no evidence to identify a growth factor that by macrophages but not by DC (61). Even allowing that one specifically supports differentiation of DC nor separates them can enrich for APC activity, the claim that DC are uniquely by guest on September 28, 2021 from the MPS. endowed with the ability to stimulate naive T cells is fundamen- tally flawed. Within the much larger macrophage population Precursors and monocyte subpopulations there are class II-positive and class II-negative cells that are able Alongside efforts to identify DC-specific growth factors, there to suppress the activation of T cells (62). Alternatively activated has been considerable effort to identify cells in bone marrow, F4/80-positive macrophages generated in parasite infection can blood, or tissues that are committed to becoming DC as op- powerfully suppress Ag-specific T cell activation (63). Simi- posed to macrophages. The lineage relationship between mac- larly, Dillon et al. (64) found that the TLR2 agonist zymosan rophages and DC in vivo was resolved with the identification of stimulated marginal zone and red pulp macrophages and gen- a common clonogenic progenitor cell in the bone marrow called erated TGF-␤-dependent suppression of T cell activation. the macrophage-DC progenitor (MDP). This cell is the precur- Among the splenic myeloid population there are so-called sor of blood monocytes and tissue macrophages and DC in inhibitory myeloid cells that express high levels of CSF-1R, F4/ many tissues (49, 50). MDP were not efficient at generating 80, CD11b, and Ly6C (65, 66), and their expansion in re- resident DC in lymphoid organs that probably proliferate lo- sponse to CSF-1 is immunosuppressive (67, 68). Interestingly, cally but gave rise to the so-called inflammatory and TNF/in- CSF-1-dependent purified F4/80-positive myeloid suppressors ducible NO synthase-producing DC (26, 49, 51, 52). The con- can differentiate into functional CD11c-positive DC when cul- clusion that many tissue CD11c-positive cells arise from blood tivated in GM-CSF (66). monocytes was supported in detailed studies of the origins of The selective removal of suppressor macrophages provides an the Langerhans cells of the and their dependence upon alternative explanation for the enrichment of APC activity in CSF-1R signaling (53). In keeping with studies on MDP in the DC fractions and the ability of the purified DC to act on naive steady state, the CD11c-positive cell populations of the spleen cells. In fact, because APC activity in the DC fraction is actually and probably the lymph node were not replenished directly not enriched above the total activity of spleen, the large major- from blood monocytes (49, 50), unlike the CD11c-positive ity of APC must reside with the “macrophages,” compromised populations of intestine and lung under the same conditions. by suppressors in the same fraction. In a typical MLR or Ag- Randolph et al. (54) suggested that monocyte fate (macrophage presentation assay, populations of APC and T cell responders vs DC) was determined following trans-endothelial migration, are all placed together in a closed system, whereas in vivo sup- but we now recognize at least two functional monocyte subsets, pressors and activators may be segregated and soluble suppres- distinguished by size and the level of expression of markers, sors may be continuously removed. Suppressive macrophages such as F4/80, Ly6C (Gr-1), CD43, and the recep- act selectively on cells that respond to low doses of mitogen tor CX3CR1. One of the most exciting observations in the field (62), and self-tolerance requires very stringent and selective 5832 BRIEF REVIEWS: THE DENDRITIC CELL MYTH control of naive or primary T cell activation. So, to activate na- system (83) and an active (CR4) that is ive T cells efficiently, it may be necessary to remove suppressor induced during macrophage maturation (84). The original de- macrophages. Aside from their ability to suppress primary T cell scription of mouse CD11c (7) detected the Ag on interdigitat- activation nonspecifically, class II MHC-positive macrophages ing cells in T cell areas. The more recent studies of CD11c- contribute Ag-specific inactivation and . In yellow fluorescent transgenic mice, focused solely on mice that lacked the macrophage-specific marker protein F4/80 the lymph node, did not support the distinction between mac- there was a failure of both inducible Ag-specific tolerance and rophages and DC (8). In fact, CD11c in the mouse is an endo- oral tolerance (69). Activated CD11b on the surface of macro- cytic receptor that is widely expressed and inducible during in- phages has also been found to generate an inhibitory signal to T flammation in macrophages, granulocytes, DC, and T cells and cells (70). Recently, Denning et al. (71) purified APCs in the has no direct role in T cell activation. The effect of a CD11c- intestinal lamina propria. In addition to conventional DC, null mutation on the pathology of experimental autoimmune there was a class II MHC-positive, CD11c- and CD11b-posi- disease is not considered to be due to any defect in Ag presen- tive cell that selectively activated CD25-positive regulatory T tation (85). cells. They did not apparently isolate the F4/80-positive, The CD11c-positive cells of the lamina propria of the gut can CD11b-negative, class II MHC positive, CD11c-positive pop- extend processes between epithelial cells and sample the lume- ulation (Fig. 1A; see also Ref. 50). These cells would likely exert nal contents (86, 87). Their location and morphology is indis- Ag-nonspecific suppression (72). tinguishable from that of the F4/80-positive, CSF-1R-positive

An additional variable to consider in studies of APC activity macrophages in Fig. 1. Vallon-Eberhard et al. (88) isolated in- Downloaded from Ϫ Ϫ in vitro is the nature of the T cell response being measured. testinal lamina propria cells from rag / mice, and identified Rothoeft et al. (73) compared APC activity of human mono- two major populations of myeloid cells, both expressing class II cyte-derived DC (grown in GM-CSF) and monocyte-derived MHC and CD11c but differing in expression of CX3CR1 and macrophages (grown in CSF-1). Both cell types clustered with CD14. Both populations expressed the macrophage marker F4/ naive T cells and formed an . The “DC” 80. In the kidney, Soos et al. (89) rediscovered the interstitial were somewhat more efficient at inducing proliferation and network of stellate F4/80-positive cells (Fig. 1B), confirmed http://www.jimmunol.org/ IL-2 and IFN-␥ production, where the “macrophages” selec- their expression of class II MHC, and showed that they express tively induced IL-4 production. CX3CR1-EGFP and CD11c. In our own array studies, CD11c is highly expressed in thioglycollate-elicited peritoneal macro- Macrophages can present Ag in a primary response phages (our unpublished observations) and, as noted below, all When we compare macrophages and DC in APC activity in of the lung macrophages express CD11c. Taken together, these vivo rather than in closed systems in vitro, the differences in data and many other studies indicate that CD11c is expressed APC activity are less compelling. Pozzi et al. (29) compared the by many macrophages in the mouse, as it is in human, especially activity of Ag-pulsed, CD11c-negative, bone marrow-derived on the macrophage population associated with epithelia and on by guest on September 28, 2021 macrophages (grown in CSF-1) and DC (grown in GM-CSF all inflammatory macrophages. plus IL-4) by direct injection into mice. Both populations mi- grated to lymph nodes and activated CD8 T cell proliferation. In contrast to the lack of stimulatory activity of the bulk pop- CD11c-diphtheria toxin receptor (DTR) transgenic depletion method ulation of splenic macrophages, McCormack et al. (74–76) proves only that CD11c-positive cells are involved in showed that cloned macrophage cells from spleen presented al- A CD11c-DTR transgenic mouse was developed as a tool to loantigen to naive CD8-positive cells. Immortalized clonal especially ablate DC (90). But, diphtheria toxin administration macrophage cell lines (CD14, F4/80, CD11b-positive), when to CD11c-DTR mice was later shown to ablate all of the mar- stimulated with IFN ␥ to induce class II MHC and pulsed with ginal zone macrophage populations of spleen and the sinusoidal Ag, could elicit Th1-polarized primary immune responses in macrophages from the lymph nodes, as well as F4/80-positive mice (77). Moser (78) also reported that Ag-pulsed macro- cells from the red pulp of spleen (91). Neuenbahn et al. (92) phages could generate primed T cells in vivo but, in comparison used the model to demonstrate that CD11c-positive cells in the to DC, selectively activated Th2 responses. Finally, extending spleen are required for infection with the macrophage-trophic the discussion above of macrophage-mediated suppression, infection Listeria monocytogenes. Inter alia, they confirm that Guan et al. (79) reported that CSF-1-treated peritoneal macro- CD11c-EGFP from the same transgene is expressed on a net- phages exerted Ag-specific suppression of alloreactivity and au- work of stellate cells in the red pulp. In the lung, van Rijt et al. toimmune responses in mice. (93) showed that the large majority of alveolar macrophages and interstitial myeloid cells in the lung express CD11c and CD11c is not a DC marker in mice or humans class II MHC and were ablated following diphtheria toxin ad- The argument as to whether macrophages can present Ag is ministration in the CD11c-DTR model. They do not appear to partly a semantic one, presuming that DC and macrophages are have analyzed the substantial population of interstitial macro- distinguishable by any marker that is not directly required for phages, identified by von Garnier et al. (94), that express both Ag-presentation. There are a number of candidate endocytic re- CD11c and F4/80 but lack class II MHC and apparently has ceptors, including DEC-205, DCL1, and DC-HIL/gpnmb, suppressive activity. that probably function in Ag uptake (31, 80, 81). The most- The use of the CD11c-DTR model indicates that CD11c- studied candidate DC marker in the mouse is the integrin positive mononuclear phagocytes are required for Ag presenta- CD11c. There is no evidence for any direct function of CD11c tion, confirms that CD11c is expressed on resident macro- in T cell activation based upon a knockout phenotype (82). phages in lung and gut, but provides no evidence that this CD11c in humans is a marker for the mononuclear phagocyte activity resides in a subset that one could classify as DC. The Journal of Immunology 5833

Markers and the infinite number of MPS subpopulations sentation, dendritic cell subsets, and the generation of immunity to cellular . Immunol. Rev. 199: 9–26. Gene expression in mammalian cells is a stochastic process, and 6. Pulendran, B. 2006. Division of labor and cooperation between dendritic cells. Nat. each individual allele at any locus has its own intrinsic proba- Immunol. 7: 699–700. 7. Metlay, J. P., M. D. Witmer-Pack, R. Agger, M. T. Crowley, D. Lawless, and bility of being induced at the level of individual cells (95, 96). R. M. Steinman. 1990. The distinct leukocyte integrins of mouse spleen dendritic cells As a consequence, surface markers commonly appear to divide as identified with new hamster monoclonal . J. Exp. Med. 171: 1753–1771. 8. Lindquist, R. L., G. Shakhar, D. Dudziak, H. Wardemann, T. Eisenreich, populations of cells into two clear sets on a FACS profile. This M. L. Dustin, and M. C. Nussenzweig. 2004. Visualizing dendritic cell networks in principal is very well illustrated by a study on the APC popula- vivo. Nat. Immunol. 5: 1243–1250. tions of the mouse uterus, which used an extensive panel of pu- 9. Hume, D. A. 2006. The mononuclear phagocyte system. Curr. Opin. Immunol. 18: 49–53. tative macrophage and DC markers as well as class II MHC 10. Gordon, S. 2007. The macrophage: past, present and future. Eur. J. Immunol. (97). Although there were three distinct populations with dis- 37(Suppl. 1): S9–S17. tinct forward and side scatter properties, namely small imma- 11. Gordon, S., and P. R. Taylor. 2005. Monocyte and macrophage heterogeneity. Nat. Rev. 5: 953–964. ture monocyte-like cells (F4/80-positive, CD11b-positive, class 12. Hume, D. A., I. L. Ross, S. R. Himes, R. T. Sasmono, C. A. Wells, and T. Ravasi. II-negative), large mature macrophages (F4/80-positive, class 2002. The mononuclear phagocyte system revisited. J. Leukocyte Biol. 72: 621–627. 13. Lichanska, A. M., and D. A. Hume. 2000. Origins and functions of phagocytes in the II-positive), and DC (F4/80-negative, class II MHC positive), embryo. Exp. Hematol. 28: 601–611. each population could be further subdivided. Similarly, a study 14. Sasmono, R. T., D. Oceandy, J. W. Pollard, W. Tong, P. Pavli, B. J. Wainwright, of myeloid cells from the Peyer’s patch showed that the CD11c- M. C. Ostrowski, S. R. Himes, and D. A. Hume. 2003. A macrophage colony-stim- ulating factor receptor-green fluorescent protein transgene is expressed throughout the positive cells could be subdivided based upon expression of F4/ mononuclear phagocyte system of the mouse. Blood 101: 1155–1163. 80, CD11b, FcR, CD44, and ICAM-1 (98). The only conclu- 15. Sasmono, R. T., A. Ehrnsperger, S. L. Cronau, T. Ravasi, R. Kandane, M. J. Hickey, Downloaded from A. D. Cook, S. R. Himes, J. A. Hamilton, and D. A. Hume. 2007. Mouse neutrophilic sion one can make from these studies is that the number of granulocytes express mRNA encoding the macrophage colony-stimulating factor re- subpopulations is an exponential function of the number of ceptor (CSF-1R) as well as many other macrophage-specific transcripts and can trans- markers, and no marker distinguishes DC from macrophages. differentiate into macrophages in vitro in response to CSF-1. J. Leukocyte Biol. 82: 111–123. 16. Sanders, A. G., H. W. Florey, and A. Q. Wells. 1951. The behaviour of intravenously Conclusion injected particles of carbon and micrococcin in normal and tuberculous tissue. The literature constructs a picture of a typical DC and emphasizes Br. J. Exp. Pathol. 32: 452–457. http://www.jimmunol.org/ 17. Markham, N. P., and H. W. Florey. 1951. The effect on experimental of its importance in every aspect of immunity (for example, see Ref. the intravenous injection of insoluble substances; experiments with carbon. Br. J. Exp. 99). Arguments are put forward to separate DC from macrophages. Pathol. 32: 25–33. For example, Serbina et al. (52) argue that the TNF-inducible NO 18. Martinez-Pomares, L., and S. Gordon. 2007. presentation the macrophage way. Cell 131: 641–643. synthase-producing DC (TipDC) in Listeria infection is not an 19. Taylor, P. R., L. Martinez-Pomares, M. Stacey, H. H. Lin, G. D. Brown, and activated macrophage because it does not express F4/80 or CD14 S. Gordon. 2005. Macrophage receptors and immune recognition. Annu. Rev. Immu- and has APC activity. It is difficult to see the distinction from nol. 23: 901–944. 20. Rae, F., K. Woods, T. Sasmono, N. Campanale, D. Taylor, D. A. Ovchinnikov, activated macrophages (19). A more sustainable view of APC ac- S. M. Grimmond, D. A. Hume, S. D. Ricardo, and M. H. Little. 2007. Characteri- sation and trophic functions of murine embryonic macrophages based upon the use of

tivity is that cells of the MPS can exist along a continuum of by guest on September 28, 2021 activities from active Ag-presenters to Ag-specific and nonspecific a Csf1r-EGFP transgene reporter. Dev. Biol. 308: 232–246. 21. Bonifer, C., and D. A. Hume. 2008. The transcriptional regulation of the colony- suppressors of T cell activation and that different T cells in turn stimulating factor 1 receptor (csf1r) gene during hematopoiesis. Front. Biosci. 13: recognize and respond to the activation state of the APC with 549–560. distinct responses. APC is not a cell type; it is a regulated activity. 22. Chitu, V., and E. R. Stanley. 2006. Colony-stimulating factor-1 in immunity and inflammation. Curr. Opin. Immunol. 18: 39–48. Even if one accepts the dogma that presentation of Ag to naive T 23. Dai, X. M., G. R. Ryan, A. J. Hapel, M. G. Dominguez, R. G. Russell, S. Kapp, cells is a specialized function of cells called DC, the evidence V. Sylvestre, and E. R. Stanley. 2002. Targeted disruption of the mouse colony-stim- reviewed herein indicates that all macrophages are “immature DC” ulating factor 1 receptor gene results in osteopetrosis, mononuclear phagocyte defi- ciency, increased primitive progenitor cell frequencies, and reproductive defects. Blood and all DC are “immature macrophages.” But in my view, DC as 99: 111–120. a separate cell type with unique capacity or destiny do not actually 24. Lin, H., E. Lee, K. Hestir, C. Leo, M. Huang, E. Bosch, R. Halenbeck, G. Wu, exist. They are simply a heterogeneous subset of mononuclear A. Zhou, D. Behrens, et al. 2008. Discovery of a and its receptor by func- tional screening of the extracellular proteome. Science 320: 807–811. phagocytes. The machinery required to present Ag to T cells is not 25. MacDonald, K. P., V. Rowe, H. M. Bofinger, R. Thomas, T. Sasmono, D. A. Hume, strictly coexpressed with any other marker. The plasticity of mono- and G. R. Hill. 2005. The colony-stimulating factor 1 receptor is expressed on den- nuclear phagocytes and their diversity may be the key to the ini- dritic cells during differentiation and regulates their expansion. J. Immunol. 175: 1399–1405. tiation, the nature, and the outcome of cellular immunity. 26. Geissmann, F., C. Auffray, R. Palframan, C. Wirrig, A. Ciocca, L. Campisi, E. Narni-Mancinelli, and G. Lauvau. 2008. Blood monocytes: distinct subsets, how they relate to dendritic cells, and their possible roles in the regulation of T-cell re- Acknowledgments sponses. Immunol. Cell Biol. 86: 398–408. Thanks to Frederic Geissmann for helpful discussion. However, the views 27. Misawa, E., T. Sakurai, M. Yamada, Y. Tamura, and K. Motoyoshi. 2004. Adminis- ϩ ϩ herein are entirely my own. tration of macrophage colony-stimulating factor mobilized both CD11b CD11c cells and NK1.1ϩ cells into peripheral blood. Int. Immunopharmacol. 4: 791–803. 28. Fancke, B., M. Suter, H. Hochrein, and M. O’Keeffe. 2008. M-CSF: a novel plasma- Disclosures cytoid and conventional dendritic cell poietin. Blood 111: 150–159. The authors have no financial conflict of interest. 29. Pozzi, L. A., J. W. Maciaszek, and K. L. Rock. 2005. Both dendritic cells and macro- phages can stimulate naive CD8 T cells in vivo to proliferate, develop effector func- tion, and differentiate into memory cells. J. Immunol. 175: 2071–2081. References 30. Irvine, K. M., C. J. Burns, A. F. Wilks, S. Su, D. A. Hume, and M. J. Sweet. 2006. A 1. Banchereau, J., and R. M. Steinman. 1998. Dendritic cells and the control of immu- CSF-1 receptor kinase inhibitor targets effector functions and inhibits pro-inflamma- nity. Nature 392: 245–252. tory cytokine production from murine macrophage populations. FASEB J. 20: 2. Steinman, R. M., and K. Inaba. 1999. Myeloid dendritic cells. J. Leukocyte Biol. 66: 1921–1923. 205–208. 31. Ripoll, V. M., K. M. Irvine, T. Ravasi, M. J. Sweet, and D. A. Hume. 2007. Gpnmb 3. Trombetta, E. S., and I. Mellman. 2005. Cell biology of in vitro is induced in macrophages by IFN-␥ and and acts as a feedback and in vivo. Annu. Rev. Immunol. 23: 975–1028. regulator of proinflammatory responses. J. Immunol. 178: 6557–6566. 4. Carbone, F. R., and W. R. Heath. 2003. The role of dendritic cell subsets in immunity 32. Inaba, K., M. Inaba, N. Romani, H. Aya, M. Deguchi, S. Ikehara, S. Muramatsu, and to . Curr. Opin. Immunol. 15: 416–420. R. M. Steinman. 1992. Generation of large numbers of dendritic cells from mouse 5. Heath, W. R., G. T. Belz, G. M. Behrens, C. M. Smith, S. P. Forehan, I. A. Parish, bone marrow cultures supplemented with /macrophage colony-stimulat- G. M. Davey, N. S. Wilson, F. R. Carbone, and J. A. Villadangos. 2004. Cross-pre- ing factor. J. Exp. Med. 176: 1693–1702. 5834 BRIEF REVIEWS: THE DENDRITIC CELL MYTH

33. Fleetwood, A. J., T. Lawrence, J. A. Hamilton, and A. D. Cook. 2007. Granulocyte- 59. Delamarre, L., M. Pack, H. Chang, I. Mellman, and E. S. Trombetta. 2005. Differ- macrophage colony-stimulating factor (CSF) and macrophage CSF-dependent mac- ential lysosomal proteolysis in antigen-presenting cells determines antigen fate. Science rophage phenotypes display differences in cytokine profiles and transcription factor 307: 1630–1634. activities: implications for CSF blockade in inflammation. J. Immunol. 178: 60. Tulone, C., J. Tsang, Z. Prokopowicz, N. Grosvenor, and B. Chain. 2007. Natural 5245–5252. cathepsin E deficiency in the of C57BL/6J mice. Immunogenetics 59: 34. Sester, D. P., A. Trieu, K. Brion, K. Schroder, T. Ravasi, J. A. Robinson, 927–935. R. C. McDonald, V. Ripoll, C. A. Wells, H. Suzuki, et al. 2005. LPS regulates a set of 61. Kakehashi, H., T. Nishioku, T. Tsukuba, T. Kadowaki, S. Nakamura, and genes in primary murine macrophages by antagonising CSF-1 action. Immunobiology K. Yamamoto. 2007. Differential regulation of the nature and functions of dendritic 210: 97–107. cells and macrophages by cathepsin E. J. Immunol. 179: 5728–5737. 35. Forrest, A. R., D. F. Taylor, M. L. Crowe, A. M. Chalk, N. J. Waddell, G. Kolle, 62. Hume, D. A., and M. J. Weidemann. 1980. Mitogenic lymphocyte transformation. G. J. Faulkner, R. Kodzius, S. Katayama, C. Wells, et al. 2006. Genome-wide review Research Monographs in Immunology, Vol. 2. Elsevier/North Holland Biomedical of transcriptional complexity in mouse protein kinases and phosphatases. Genome Press, New York, pp. 46–47. ϩ Biol. 7: R5. 63. Taylor, M. D., A. Harris, M. G. Nair, R. M. Maizels, and J. E. Allen. 2006. F4/80 ϩ 36. Wells, C. A., A. M. Chalk, A. Forrest, D. Taylor, N. Waddell, K. Schroder, alternatively activated macrophages control CD4 T cell hyporesponsiveness at sites S. R. Himes, G. Faulkner, S. Lo, T. Kasukawa, et al. 2006. Alternate transcription of peripheral to filarial infection. J. Immunol. 176: 6918–6927. the Toll-like receptor signaling cascade. Genome Biol. 7: R10. 64. Dillon, S., S. Agrawal, K. Banerjee, J. Letterio, T. L. Denning, K. Oswald-Richter, 37. Schroder, K., P. J. Hertzog, T. Ravasi, and D. A. Hume. 2004. -␥: an over- D. J. Kasprowicz, K. Kellar, J. Pare, T. van Dyke, et al. 2006. Yeast zymosan, a stim- view of signals, mechanisms and functions. J. Leukocyte Biol. 75: 163–189. ulus for TLR2 and dectin-1, induces regulatory antigen-presenting cells and immu- 38. Breen, F. N., D. A. Hume, and M. J. Weidemann. 1991. Interactions among granu- nological tolerance. J. Clin. Invest. 116: 916–928. locyte-macrophage colony-stimulating factor, macrophage colony-stimulating factor, 65. Bronte, V., E. Apolloni, A. Cabrelle, R. Ronca, P. Serafini, P. Zamboni, N. P. Restifo, ␥ and P. Zanovello. 2000. Identification of a CD11bϩ/Gr-1ϩ/CD31ϩ myeloid pro- and IFN- lead to enhanced proliferation of murine macrophage progenitor cells. ϩ J. Immunol. 147: 1542–1547. genitor capable of activating or suppressing CD8 T cells. Blood 96: 3838–3846. 39. Maraskovsky, E., K. Brasel, M. Teepe, E. R. Roux, S. D. Lyman, K. Shortman, and 66. Li, Q., P. Y. Pan, P. Gu, D. Xu, and S. H. Chen. 2004. Role of immature myeloid ϩ H. J. McKenna. 1996. Dramatic increase in the numbers of functionally mature den- Gr-1 cells in the development of antitumor immunity. Cancer Res. 64: 1130–1139. 67. Sakurai, T., N. Wakimoto, M. Yamada, S. Shimamura, and K. Motoyoshi. 1998. dritic cells in Flt3 ligand-treated mice: multiple dendritic cell subpopulations identi- Downloaded from fied. J. Exp. Med. 184: 1953–1962. Effect of macrophage colony-stimulating factor (M-CSF) on mouse immune re- 40. McKenna, H. J., K. L. Stocking, R. E. Miller, K. Brasel, T. De Smedt, sponses in vivo. Immunopharmacol. Immunotoxicol. 20: 79–102. E. Maraskovsky, C. R. Maliszewski, D. H. Lynch, J. Smith, B. Pulendran, et al. 2000. 68. Doyle, A. G., W. J. Halliday, C. J. Barnett, T. L. Dunn, and D. A. Hume. 1992. Effect Mice lacking flt3 ligand have deficient hematopoiesis affecting hematopoietic progen- of recombinant human macrophage colony-stimulating factor 1 on immunopathol- itor cells, dendritic cells, and natural killer cells. Blood 95: 3489–3497. ogy of experimental brucellosis in mice. Infect. Immun. 60: 1465–1472. 41. D’Amico, A., and L. Wu. 2003. The early progenitors of mouse dendritic cells and 69. Lin, H. H., D. E. Faunce, M. Stacey, A. Terajewicz, T. Nakamura, J. Zhang-Hoover, plasmacytoid predendritic cells are within the bone marrow hemopoietic precursors M. Kerley, M. L. Mucenski, S. Gordon, and J. Stein-Streilein. 2005. The macrophage expressing Flt3. J. Exp. Med. 198: 293–303. F4/80 receptor is required for the induction of antigen-specific efferent regulatory T 42. Walzer, T., P. Brawand, D. Swart, J. Tocker, and T. De Smedt. 2005. No defect in cells in peripheral tolerance. J. Exp. Med. 201: 1615–1625. http://www.jimmunol.org/ T-cell , secondary response, or tolerance induction in response to inhaled an- 70. Varga, G., S. Balkow, M. K. Wild, A. Stadtbaeumer, M. Krummen, T. Rothoeft, tigens in Fms-like tyrosine kinase 3 ligand-deficient mice. J. Clin. Immunol. T. Higuchi, S. Beissert, K. Wethmar, K. Scharffetter-Kochanek, et al. 2007. Active 115: 192–199. MAC-1 (CD11b/CD18) on DCs inhibits full T-cell activation. Blood 109: 661–669. 43. Wells, C. A., T. Ravasi, and D. A. Hume. 2005. Inflammation suppressor genes: 71. Denning, T. L., Y. C. Wang, S. R. Patel, I. R. Williams, and B. Pulendran. 2007. please switch out all the lights. J. Leukocyte Biol. 78: 9–13. Lamina propria macrophages and dendritic cells differentially induce regulatory and 17-producing T cell responses. Nat. Immunol. 8: 1086–1094. 44. Hausser, G., B. Ludewig, H. R. Gelderblom, Y. Tsunetsugu-Yokota, K. Akagawa, and A. Meyerhans. 1997. Monocyte-derived dendritic cells represent a transient stage of 72. Pavli, P., C. E. Woodhams, W. F. Doe, and D. A. Hume. 1990. Isolation and char- differentiation in the myeloid lineage. Immunobiology 197: 534–542. acterization of antigen-presenting dendritic cells from the mouse intestinal lamina propria. Immunology 70: 40–47. 45. Lo, A. S., P. Gorak-Stolinska, V. Bachy, M. A. Ibrahim, D. M. Kemeny, and J. Maher. 73. Rothoeft, T., A. Gonschorek, H. Bartz, O. Anhenn, and U. Schauer. 2003. Antigen 2007. Modulation of dendritic cell differentiation by colony-stimulating factor-1: role Ј dose, type of antigen-presenting cell and time of differentiation contribute to the T of phosphatidylinositol 3 -kinase and delayed caspase activation. J. Leukocyte Biol. 82: by guest on September 28, 2021 helper 1/T helper 2 polarization of naive T cells. Immunology 110: 430–439. 1446–1454. 74. McCormack, J. M., D. Askew, and W. S. Walker. 1993. Alloantigen presentation by 46. Palucka, K. A., N. Taquet, F. Sanchez-Chapuis, and J. C. Gluckman. 1998. Dendritic individual clones of mouse splenic macrophages. Selective expression of IL-1 ␣ in re- cells as the terminal stage of monocyte differentiation. J. Immunol. 160: 4587–4595. ϩ sponse to CD8 T cell-derived IFN-␥ defines the alloantigen-presenting phenotype. 47. Robinson, S. P., S. Patterson, N. English, D. Davies, S. C. Knight, and C. D. Reid. J. Immunol. 151: 5218–5227. 1999. Human peripheral blood contains two distinct lineages of dendritic cells. Eur. 75. McCormack, J. M., S. C. Moore, J. W. Gatewood, and W. S. Walker. 1992. Mouse J. Immunol. 29: 2769–2778. ϩ splenic macrophage cell lines with different antigen-presenting activities for CD4 48. Mollah, Z. U., S. Aiba, S. Nakagawa, M. Hara, H. Manome, M. Mizuashi, T. Ohtani, helper T cell subsets and allogeneic CD8ϩ T cells. Cell. Immunol. 145: 359–371. Y. Yoshino, and H. Tagami. 2003. Macrophage colony-stimulating factor in cooper- ␤ ϩ 76. McCormack, J. M., D. Sun, and W. S. Walker. 1991. A subset of mouse splenic mac- ation with transforming growth factor- 1 induces the differentiation of CD34 he- rophages can constitutively present alloantigen directly to CD8ϩ T cells. J. Immunol. matopoietic progenitor cells into Langerhans cells under serum-free conditions with- 147: 421–427. out granulocyte-macrophage colony-stimulating factor. J. Invest. Dermatol. 120: 77. Desmedt, M., P. Rottiers, H. Dooms, W. Fiers, and J. Grooten. 1998. Macrophages 256–265. induce cellular immunity by activating Th1 cell responses and suppressing Th2 cell 49. Fogg, D. K., C. Sibon, C. Miled, S. Jung, P. Aucouturier, D. R. Littman, A. Cumano, responses. J. Immunol. 160: 5300–5308. and F. Geissmann. 2006. A clonogenic bone marrow progenitor specific for macro- 78. Moser, M. 2001. Regulation of Th1/Th2 development by antigen-presenting cells in phages and dendritic cells. Science 311: 83–87. vivo. Immunobiology 204: 551–557. 50. Varol, C., L. Landsman, D. K. Fogg, L. Greenshtein, B. Gildor, R. Margalit, 79. Guan, Y., S. Yu, Z. Zhao, B. Ciric, G. X. Zhang, and A. Rostami. 2007. Antigen V. Kalchenko, F. Geissmann, and S. Jung. 2007. Monocytes give rise to mucosal, but presenting cells treated in vitro by macrophage colony-stimulating factor and autoan- not splenic, conventional dendritic cells. J. Exp. Med. 204: 171–180. tigen protect mice from . J. Neuroimmunol. 192: 68–78. 51. Geissmann, F. 2007. The origin of dendritic cells. Nat. Immunol. 8: 558–560. 80. Jiang, W., W. J. Swiggard, C. Heufler, M. Peng, A. Mirza, R. M. Steinman, and 52. Serbina, N. V., T. P. Salazar-Mather, C. A. Biron, W. A. Kuziel, and E. G. Pamer. M. C. Nussenzweig. 1995. The receptor DEC-205 expressed by dendritic cells and 2003. TNF/iNOS-producing dendritic cells mediate innate immune defense against thymic epithelial cells is involved in antigen processing. Nature 375: 151–155. bacterial infection. Immunity 19: 59–70. 81. Kato, M., S. Khan, E. d’Aniello, K. J. McDonald, and D. N. Hart. 2007. The novel 53. Ginhoux, F., F. Tacke, V. Angeli, M. Bogunovic, M. Loubeau, X. M. Dai, endocytic and phagocytic C-Type lectin receptor DCL-1/CD302 on macrophages is E. R. Stanley, G. J. Randolph, and M. Merad. 2006. Langerhans cells arise from colocalized with F-actin, suggesting a role in cell adhesion and migration. J. Immunol. monocytes in vivo. Nat. Immunol. 7: 265–273. 179: 6052–6063. 54. Randolph, G. J., S. Beaulieu, S. Lebecque, R. M. Steinman, and W. A. Muller. 1998. 82. Wu, H., J. R. Rodgers, X. Y. Perrard, J. L. Perrard, J. E. Prince, Y. Abe, B. K. Davis, Differentiation of monocytes into dendritic cells in a model of transendothelial traf- G. Dietsch, C. W. Smith, and C. M. Ballantyne. 2004. Deficiency of CD11b or ficking. Science 282: 480–483. CD11d results in reduced staphylococcal enterotoxin-induced T cell response and T 55. Auffray, C., D. Fogg, M. Garfa, G. Elain, O. Join-Lambert, S. Kayal, S. Sarnacki, cell phenotypic changes. J. Immunol. 173: 297–306. A. Cumano, G. Lauvau, and F. Geissmann. 2007. Monitoring of blood vessels and 83. Hogg, N., L. Takacs, D. G. Palmer, Y. Selvendran, and C. Allen. 1986. The p150,95 tissues by a population of monocytes with patrolling behavior. Science 317: 666–670. molecule is a marker of human mononuclear phagocytes: comparison with expression 56. Jakubzick, C., F. Tacke, F. Ginhoux, A. J. Wagers, N. van Rooijen, M. Mack, of class II molecules. Eur. J. Immunol. 16: 240–248. M. Merad, and G. J. Randolph. 2008. Blood monocyte subsets differentially give rise 84. Myones, B. L., J. G. Dalzell, N. Hogg, and G. D. Ross. 1988. and mono- ϩ Ϫ to CD103 and CD103 pulmonary dendritic cell populations. J. Immunol. 180: cyte cell surface p150,95 has iC3b-receptor (CR4) activity resembling CR3. J. Clin. 3019–3027. Invest. 82: 640–651. 57. Yrlid, U., C. D. Jenkins, and G. G. MacPherson. 2006. Relationships between distinct 85. Bullard, D. C., X. Hu, J. E. Adams, T. R. Schoeb, and S. R. Barnum. 2007. p150/95 blood monocyte subsets and migrating intestinal lymph dendritic cells in vivo under (CD11c/CD18) expression is required for the development of experimental autoim- steady-state conditions. J. Immunol. 176: 4155–4162. mune encephalomyelitis. Am. J. Pathol. 170: 2001–2008. 58. Steinman, R. M., and M. D. Witmer. 1978. Lymphoid dendritic cells are potent stim- 86. Chieppa, M., M. Rescigno, A. Y. Huang, and R. N. Germain. 2006. Dynamic imag- ulators of the primary mixed leukocyte reaction in mice. Proc. Natl. Acad. Sci. USA 75: ing of dendritic cell extension into the small bowel lumen in response to epithelial cell 5132–5136. TLR engagement. J. Exp. Med. 203: 2841–2852. The Journal of Immunology 5835

87. Hapfelmeier, S., A. J. Muller, B. Stecher, P. Kaiser, M. Barthel, K. Endt, M. Eberhard, challenge abrogates the characteristic features of asthma. J. Exp. Med. 201: R. Robbiani, C. A. Jacobi, M. Heikenwalder, et al. 2008. Microbe sampling by mu- 981–991. ⌬ cosal dendritic cells is a discrete, MyD88-independent step in invG S. Typhimurium 94. von Garnier, C., L. Filgueira, M. Wikstrom, M. Smith, J. A. Thomas, colitis. J. Exp. Med. 205: 437–450. D. H. Strickland, P. G. Holt, and P. A. Stumbles. 2005. Anatomical location deter- 88. Vallon-Eberhard, A., L. Landsman, N. Yogev, B. Verrier, and S. Jung. 2006. Trans- mines the distribution and function of dendritic cells and other APCs in the respira- epithelial pathogen uptake into the small intestinal lamina propria. J. Immunol. 176: tory tract. J. Immunol. 175: 1609–1618. 2465–2469. 89. Soos, T. J., T. N. Sims, L. Barisoni, K. Lin, D. R. Littman, M. L. Dustin, and 95. Hume, D. A. 2000. Probability in transcriptional regulation and its implications for P. J. Nelson. 2006. CX3CR1ϩ interstitial dendritic cells form a contiguous network leukocyte differentiation and inducible gene expression. Blood 96: 2323–2328. throughout the entire kidney. Kidney Int. 70: 591–596. 96. Ravasi, T., C. Wells, A. Forest, D. M. Underhill, B. J. Wainwright, A. Aderem, 90. Jung, S., D. Unutmaz, P. Wong, G. Sano, K. De los Santos, T. Sparwasser, S. Wu, S. Grimmond, and D. A. Hume. 2002. Generation of diversity in the innate immune S. Vuthoori, K. Ko, F. Zavala, et al. 2002. In vivo depletion of CD11cϩ dendritic cells system: macrophage heterogeneity arises from gene-autonomous transcriptional prob- ϩ abrogates priming of CD8 T cells by exogenous cell-associated antigens. Immunity ability of individual inducible genes. J. Immunol. 168: 44–50. 17: 211–220. 97. Keenihan, S. N., and S. A. Robertson. 2004. Diversity in phenotype and steroid hor- 91. Probst, H. C., K. Tschannen, B. Odermatt, R. Schwendener, R. M. Zinkernagel, and mone dependence in dendritic cells and macrophages in the mouse uterus. Biol. Re- M. Van Den Broek. 2005. Histological analysis of CD11c-DTR/GFP mice after in prod. 70: 1562–1572. vivo depletion of dendritic cells. Clin. Exp. Immunol. 141: 398–404. 98. Ruedl, C., C. Rieser, G. Bock, G. Wick, and H. Wolf. 1996. Phenotypic and func- 92. Neuenhahn, M., K. M. Kerksiek, M. Nauerth, M. H. Suhre, M. Schiemann, ϩ F. E. Gebhardt, C. Stemberger, K. Panthel, S. Schroder, T. Chakraborty, et al. 2006. tional characterization of CD11c dendritic cell population in mouse Peyer’s patches. CD8␣ϩ dendritic cells are required for efficient entry of Listeria monocytogenes into the Eur. J. Immunol. 26: 1801–1806. spleen. Immunity 25: 619–630. 99. Ueno, H., E. Klechevsky, R. Morita, C. Aspord, T. Cao, T. Matsui, T. Di Pucchio, 93. van Rijt, L. S., S. Jung, A. Kleinjan, N. Vos, M. Willart, C. Duez, H. C. Hoogsteden, J. Connolly, J. W. Fay, V. Pascual, et al. 2007. Dendritic cell subsets in health and and B. N. Lambrecht. 2005. In vivo depletion of lung CD11cϩ dendritic cells during disease. Immunol. Rev. 219: 118–142. Downloaded from http://www.jimmunol.org/ by guest on September 28, 2021