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Unravelling Mononuclear Phagocyte Heterogeneity

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Unravelling Mononuclear Phagocyte Heterogeneity PERSPECTIVES phenotypical modulation7. Even in the VIEWPOINT absence of inflammation and infection, macrophage populations8 display bewildering Unravelling mononuclear phagocyte heterogeneity. For example, numerous mono­ nuclear phagocyte populations are found in heterogeneity the mouse spleen, including red and white pulp macrophages, ‘reservoirs’ of mobilizable monocytes9, marginal zone metallophilic Frédéric Geissmann, Siamon Gordon, David A. Hume, Allan M. Mowat and macrophages and outer zone macrophages, Gwendalyn J. Randolph and further complexity arises from the presence of resident, motile and migratory Abstract | When Ralph Steinman and Zanvil Cohn first described dendritic cells activated DCs in the same organ10. (DCs) in 1973 it took many years to convince the immunology community that Another problem is the marked hetero­ these cells were truly distinct from macrophages. Almost four decades later, the geneity in the turnover and variable lifespan DC is regarded as the key initiator of adaptive immune responses; however, of macrophages — hours to weeks — distinguishing DCs from macrophages still leads to confusion and debate in the depending on stimulation, programmed cell death and/or injury. In the mouse, field. Here, Nature Reviews Immunology asks five experts to discuss the issue of genetic manipulation and intravital imaging heterogeneity in the mononuclear phagocyte system and to give their opinion on methods make it possible to study direct the importance of defining these cells for future research. precursor–product relationships. However, the dynamics of tissue populations in humans remain largely unexplored. Myeloid cells are infamously Recent in vivo experiments in mice have heterogeneous. Do you think that this increased our understanding of the develop­ Gwendalyn J. Randolph. Yes, there is has led to confusion in the field when ment and functions of DC and macrophage confusion. However, I think the confusion discriminating between macrophages and subsets1,12,15,64,65 and should reduce confu­ can be resolved when the right considera­ dendritic cells (DCs)? sion. However, despite this progress in mice, tions are given. First, confusion should be corresponding human subsets are yet to minimal when spleen and lymph nodes are Frédéric Geissmann. Most cells types be characterized. Numerous studies have considered. In these locations, where his­ in the body are identified by their origin, attempted to recapitulate some of the hetero­ torically the pioneering work on DCs and anatomical location, function, and pheno­ geneity of human DCs and macrophages to some extent macrophages has centred, it type. Myeloid cells are arguably no more in vitro. However, in vitro differentiation of is clear that CD11chi mononuclear phago­ heterogeneous than other cell types (such blood monocytes or bone marrow cells does cytes are DCs rather than macrophages. An as lymphoid cells or epithelial cells), and not recapitulate in vivo differentiation. For abundance of recent evidence confirms that therefore heterogeneity may not be solely example, Langerhans cells and microglial cells spleen and lymph node DCs are function­ responsible for the confusion between may not renew from bone marrow2–4. ally distinct from macrophages, do not arise macrophages and DCs. from monocytes, and share fewer properties Confusion has arisen in part from the Siamon Gordon. As far as mononuclear with monocytes than macrophages do11–17. use of nonspecific cell surface markers, myeloid cells are concerned, I recognize a So here is where I see the contemporary such as CD11c (also known as αX integrin), family of closely related cells with a common confusion arising. DCs and macrophages in as a surrogate for function, anatomical origin, which branches into irreversibly dif­ non­lymphoid organs are poorly character­ location, and lineage. This has led to the ferentiated sublineages, such as macrophages, ized compared with their lymphoid tissue name ‘DC’ being used for several cell DCs and osteoclasts5. counterparts. At last, work in vivo on macro­ types, including bona fide classical DCs, as Part of the confusion in the field arises phage and DC biology in non­lymphoid well as activated monocytes, tissue macro­ from the adaptability and plasticity of organs is intense. Many of us have assumed phages, interferon (IFN)­producing cells macrophages. As a result of their extensive that the same set of markers that defini­ and even some natural killer (NK) cells and receptor repertoire and versatile biosynthetic tively distinguish DCs from macrophages eosinophils. capacity, they are highly responsive to the in lymphoid organs will also apply in non­ microheterogeneity present in different lymphoid organs, but it is turning out that Confusion has arisen in part tissue environments6. Furthermore, follow­ this premise is not true. So, I think the main ing constitutive or inflammation­induced confusion arises when scientists assume that from the use of nonspecific cell migration between different compart­ what is true in lymphoid organs is also true in surface markers ments of the body, they undergo marked non­lymphoid organs and what is true under NATURE REVIEWS | IMMUNOLOGY VOLUME 10 | JUNE 2010 | 453 © 2010 Macmillan Publishers Limited. All rights reserved PERSPECTIVES The contributors mononuclear phagocytes in the gut wall, for example, are monocyte­derived, F4/80+ and Frédéric Geissmann gained a medical degree in 1996 and a Ph.D. in immunology in 1999, both from express the macrophage colony­stimulating the University of Paris, France. After a postdoctoral fellowship with D. Littman in New York, USA, he factor 1 receptor (CSF1R; also known as started his own lab in Paris (the Unit 838 of Inserm) to study the in vivo development and functions CD115) and all the known endocytic recep­ of cells of the ‘mononuclear phagocyte system’ and their roles in the pathogenesis of inflammatory 26–28 disorders. He moved his lab to London, UK, in 2008 and is currently the Arc Chair of inflammation tors ; they have even been said to ‘resemble 26 Biology at King’s College, London, and the head of the newly established Centre for Molecular and macrophages’ . But they have been termed Cellular Biology of Inflammation. DCs solely because they express CD11c. And that really does confuse the field. Siamon Gordon is an Emeritus Professor of Cellular Pathology at the University of Oxford, UK. He obtained his medical degree at the University of Cape Town, South Africa, in 1961 and a Ph.D. at Allan M. Mowat. In my own field of Rockefeller University, New York, USA, in 1971, under the tutorage of Z. A. Cohn. Since 1976, he has mucosal immunology, myeloid cell hetero­ been at the Sir William Dunn School of Pathology at the University of Oxford, retiring from the geneity has led to considerable confusion, Glaxo–Wellcome Professorship of Cellular Pathology in 2008. He spent a sabbatical at the US National and many accepted truths probably need Institute of Allergy and Infectious Diseases (NIAID) and the US National Cancer Institute (NCI). to be re­interpreted. In the gut, there are David A. Hume (F.R.S.E.) is Director of The Roslin Institute and Research Director of the Royal (Dick) extraordinary numbers of cells of myeloid School of Veterinary Studies at the University of Edinburgh, UK. He is an international authority on origin present in the absence of inflamma­ macrophage differentiation and the function of macrophages in infection, inflammatory disease tion. There is a consensus that both macro­ and cancer. He is especially interested in transcriptional regulation, transcriptional networks and phages and DCs in the gut are generally the evolution of macrophage biology across vertebrate species. He did his Ph.D. at the Australian hyporesponsive29,30, and this overall conclu­ National University, Canberra, Australia, and his postdoctoral work with S. Gordon at the University sion holds irrespective of what one calls of Oxford in the early 1980s. Before coming to Edinburgh, he was at the Institute for Molecular the cells, but recent years have introduced Bioscience at the University of Queensland, Australia, where he was Director of the Australian increasing complexity, particularly in terms Research Council Special Research Centre for Functional and Applied Genomics. of DC biology31. More and more individual DC subsets Allan M. Mowat is Professor of Mucosal Immunology at the University of Glasgow, UK, where his laboratory is engaged in studies of macrophages and dendritic cells in the mouse intestinal mucosa. have been defined based, for example, on He is also involved in a large amount of undergraduate teaching and contributes to textbooks in their ability to induce the differentiation of general and mucosal immunology. T helper 17 (TH17) cells or forkhead box p3 + (FOXP3) regulatory T (TReg) cells, promote Gwendalyn J. Randolph completed her Ph.D. at the State University of New York in Stony Brook, IgA class­switching in B cells or produce New York, USA, in pathology and immunology. She then carried out postdoctoral research at the pro­inflammatory factors, such as tumour Rockefeller University and Weill Medical College of Cornell University, New York. She is now necrosis factor (TNF), interleukin­23 (IL­23) Professor in the Department of Gene and Cell Medicine and a member of the Immunology Institute and nitric oxide (NO)27,29,32–34. Almost with­ at Mount Sinai School of Medicine, New York. Her laboratory focuses on the trafficking of out exception, it is claimed that specific
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