White blood cells or leukocytes are a diverse group of cell types that mediate the body's immune response. They circulate through the blood and lymphatic system and are recruited to sites of tissue damage and infection. Leukocyte subsets are distinguished by functional and physical characteristics. They have a common origin in hematopoietic stem cells and develop along distinct differentiation pathways in response to internal and external cues. The mononuclear phagocyte system represents a subgroup of leucocytes originally described as a population of bone marrow-derived myeloid cells that circulate in the blood as monocytes and populate tissues as macrophages in the steady state and during inflammation (1
). In different tissues they can show significant heterogeneity with respect to phenotype, homeostatic turnover and function. The discovery of dendritic cells (DCs) as a distinct lineage of mononuclear phagocytes, specialized in antigen presentation to T cells and the initiation and control of immunity (2
), revealed additional roles of these cells in shaping the immune response to pathogens, vaccines and tumors, as well as additional heterogeneity. Whereas a detailed map of the relationship between monocytes, DCs and their progenitors begins to emerge, other areas like the origin and renewal of tissue macrophage subsets remain less defined.
() circulate in the blood, bone marrow, and spleen and do not proliferate in a steady state (3
). Monocytes represent immune effector cells, equipped with chemokine receptors and pathogen recognition receptors that mediate migration from blood to tissues during infection. They produce inflammatory cytokines and take up cells and toxic molecules. They can also differentiate into inflammatory DCs or macrophages during inflammation, and possibly, less efficiently, in the steady state. Migration to tissues and differentiation to inflammatory DC and macrophages is likely determined by the inflammatory milieu and pathogen associated pattern recognition receptors (5
Fig. 1 (A). Still frames from time-lapse intravital confocal microscopy of a crawling monocytes (arrow) and perivascular macrophages in the dermis (courtesy of F. Geissmann, for details see (52)) (B). Confocal microscopy image of the spleen from mice grafted (more ...) Macrophages
() are resident phagocytic cells in lymphoid and non-lymphoid tissues, and are believed to be involved in steady-state tissue homeostasis via the clearance of apoptotic cells, and the production of growth factors. Macrophages are equipped with a broad range of pathogen recognition receptors that make them efficient at phagocytosis and induce production of inflammatory cytokines (6
). The developmental origin and the function of tissue macrophage subsets, such as microglia (macrophages in the central nervous system), dermal macrophages (), and splenic marginal zone and metallophilic macrophages (), remain insufficiently understood.
(cDCs) () are specialized antigen-processing and presenting cells, equipped with high phagocytic activity as immature cells and high cytokine producing capacity as mature cells (7
). Although present in human circulation, cDCs are rare in mouse blood. cDCs are highly migratory cells that can move from tissues to the T-cell and B-cell zones of lymphoid organs via afferent lymphatics and high endothelial venules. cDCs regulate T cell responses both in the steady-state and during infection. They are generally short-lived and replaced by blood-borne precursors () (9
). Of note, they are distinct from Langerhans cells (LCs, DCs found in the epidermis) (), which are not replaced by blood-borne cells at the steady state (11
). Individual myeloid cell populations may share features of DC and macrophages and can be difficult to ascribe to one or the other cell type ().
(PDCs) differ from cDCs in that they are relatively long lived and a proportion of them carry characteristic immunoglobulin rearrangements (12
). They are present in the bone marrow and all peripheral organs. PDCs are specialized to respond to viral infection with a massive production of type I interferons (IFN), however, they also can act as antigen presenting cells and control T cell responses(13
The development of the mononuclear phagocyte system is controlled by cytokines - small secreted proteins that promote cell-cell communication and can act as growth and differentiation factors. The generation of monocytes, macrophages and - to some extent - DCs is dependent on the cytokine and hematopoietic growth factor receptor Csf1r (c-fms, M-CSFR, CD115), expressed in monocytes, macrophages, and mononuclear phagocyte precursors (14
). Characterization of op/op
mice, a spontaneous mutant lacking a functional Csf1
gene, has revealed both the role of Csf1 in the development of mononuclear phagocytes, and also their broad functions. (17
). The known ligands of Csf1r, Csf1/M-CSF (18
)and interleukin (IL)-34 (19
), are likely both important for the development of the mononuclear phagocyte lineage, as M-CSF-deficient mice have a milder phenotype than Csf1r-deficient mice. Another cytokine receptor closely related to Csf1r, fms-related tyrosine kinase 3 (FLT3 also known as Flk2) receptor, is critical for the development of cDCs and PDCs (10
Following on the early work on Csf1r, a large amount of work has been devoted in the past 20 years to investigating the origin and differentiation pathways of monocytes, macrophages, and DCs. This recently culminated in a series of studies that unveiled what is likely to be the main pathway for the development of DCs, monocytes and macrophages from bone marrow progenitors both in the steady state and during inflammation.