Macrophages 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 Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on September 28, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts 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 phagocyte system (MPS) is a family of cells type that is specialized for the presentation of Ag to that comprises committed precursors in the bone marrow, cir- naive T cells. Considerable effort has been applied to culating blood monocytes, 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 lymphocytes), 2008, 181: 5829–5835. granulocytes (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 lymphocyte 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 thymus 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; macrophage-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 monocyte stage; and granulocytes can be transformed into mac- cells in the spleen 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 T cell 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 lung 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 phagocytes 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).