ReviewHuman mononuclear phagocyte system reunited
Introduction
Dendritic cells (DCs), monocytes and macrophages are a heterogeneous population of mononuclear cells that are specialized in antigen processing and presentation to initiate and regulate immune responses (reviewed in [1], [2], [3]). In addition to their afferent sentinel functions, DCs and macrophages are also coordinators and effectors of homeostasis and inflammation in peripheral tissues [4], [5], [6]. There has been a paradigm shift in our understanding of mononuclear phagocytes beyond the traditional view of DCs and macrophages as functional variations of monocytes. Significant progress has been made in understanding human and mouse mononuclear phagocyte biology in tandem, including a number of important recent conceptual advances concerning their ontogeny and development (reviewed in [7], [8], [9], [10], [11]). An exceptionally fruitful strategy to integrate these findings has been comparative analysis of mouse and human, which has identified homologous subsets and facilitated a unified classification of mononuclear phagocytes across species [12], [13], [14], [15], [16], [17], [18], [19], [20].
While harnessing DCs and macrophages for therapeutic purposes has major implications for infectious disease, vaccine science, transplantation, tolerance induction, inflammation and cancer immunotherapy, the use of monocyte-derived DCs in therapy has so far been underwhelming (reviewed in [21], [22]). A thorough understanding of the origin and immune function of human mononuclear phagocytes in vivo may direct our attentions to more effective therapeutic strategies.
Section snippets
The mononuclear phagocyte family
Mononuclear phagocytes, in contrast to polymorphonuclear granulocytes (originally known as microphages), are leukocytes with specialized antigen processing and presentation function. They are found in almost all tissue compartments, including peripheral blood and are often referred to as antigen presenting cells (APCs). The ‘mononuclear phagocyte system’ was proposed in the late 1960s by van Furth to include circulating monocytes and tissue macrophages [23], the latter assumed to be
Non-lymphoid tissue
Although epidermal Langerhans cells (LCs) were first described in 1868[54], their identity as a member of the mononuclear phagocyte system was not appreciated until 1977, when they were found to express MHC Class II and complement receptors [55], [56], [57]. A notable property of some mononuclear phagocytes and lymphocytes from the skin is their ability to migrate spontaneously from skin explants cultured ex vivo [58], [59], [60], [61]. Spontaneous migration which occurs over 1–3 days from
Murine homologs of human mononuclear phagocytes
Recent comparative studies have provided a framework to unify the classification of mononuclear phagocytes between humans, mice and other species. Homologous subsets were identified by transcriptome profile, function and phenotype analysis. Human CD141+ DCs are homologous to mouse CD8/CD103+ DCs. Several markers including XCR1 [90], NECL2/CADM1 [91], TLR3 [92] and CLEC9A [69], [93], [94] are conserved across species. Ongoing research is focused on testing these antigens as universal markers for
CD141+ myeloid DCs (cDC1)
CD141+ DCs secrete TNFα, CXCL10 and IFNλ but little IL-12p70, in contrast to monocyte-derived DCs [17], [146], [147]. The homology of CD141+ DCs to murine CD8+/CD103+ DCs suggested potent cross-presentation function for this subset. CD141+ DCs have been shown to be superior at cross-presenting necrotic cell-derived and soluble antigen via CLEC9A [13], [94] and upon TLR3 stimulation with poly I:C [13], [15], [16], [17] in vitro. However, in vitro cross-presentation function is not restricted to
Conclusions
There has been tremendous progress in our understanding of the human mononuclear phagocyte network and function in recent years. The application of unbiased transcriptome profiling, comprehensive analysis of tissue, blood and bone marrow, and the iterative inter-species comparisons between human and mouse has provided the means and resolution to interrogate the complexity and heterogeneity of mononuclear phagocytes in human. However, there are still known unknowns and unknown unknowns, which
Acknowledgements
We would like to acknowledge funding from the Wellcome Trust (WT088555 to M.H. and WT101155/Z/13/Z to V.B.), British Skin Foundation, Leukaemia Research, the Histiocytosis Association and Bright Red.
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