Dendritic cells, monocytes and macrophages: a unified nomenclature based on ontogeny

Abstract

The mononuclear phagocyte system (MPS) has historically been categorized into monocytes, dendritic cells and macrophages on the basis of functional and phenotypical characteristics. However, considering that these characteristics are often overlapping, the distinction between and classification of these cell types has been challenging. In this Opinion article, we propose a unified nomenclature for the MPS. We suggest that these cells can be classified primarily by their ontogeny and secondarily by their location, function and phenotype. We believe that this system permits a more robust classification during both steady-state and inflammatory conditions, with the benefit of spanning different tissues and across species.

Figure 1. A decision tree to facilitate nomenclature decisions for mononuclear phagocytes

We propose that mononuclear phagocytes would primarily be categorized according to their ontog eny (level one nomenclature). Although the ontogenetic nomenclature aims to prevent the mis-categorization of cells, we fully acknowledge that studies pertaining to cellular origin are not always feasible. Furthermore, adopting an ontogeny-based nomenclature for mononuclear phagocytes in other species, such as humans, remains challenging. We suggest that when cell transfers are unfeasible and fate-mapping or genetic ablation models are not available, a parallel nomenclature should be used. This level two nomenclature will identify mononuclear phagocyte subsets on the basis of their expression of conserved phenotypical markers or transcripts (not shown). See Supplementary Information S1 (table) and S2 (table) for details of the markers that can be used to aid classification decisions in mice and humans. Cells of embryonic origin would be referred to as ‘macrophages’ (orange box). Note that some macrophages have historical names such as ‘Langerhans cells’, ‘Kupffer cells’ or ‘microglia’ and we propose to keep these terms. Others would be categorized as, for example, ‘peritoneal macrophages’ or ‘alveolar macrophages’. Mononuclear phagocyte system (MPS) cells of uncertain origin would be referred to as ‘mononuclear phagocytes’ (red box) and be further categorized on the basis of their functional or phenotypical properties and their tissue localization (level two classification). This aims to prevent the miscategorization of MPS cells and should facilitate scientific communication. MPS cells derived from monocytes would be referred to as ‘monocyte-derived cells’ (blue box). Note that these cells are very plastic and can acquire functional properties of both dendritic cells (DCs) and macrophages in some settings. Monocyte-derived cells would be further categorized according to functional specialization, phenotypical properties and transcriptional networks under level two nomenclature. Monocytes, DCs and macrophages were historically grouped in the MPS (see Box 1), and for continuity, we propose to maintain this classification. Hypothetically, if a new immune cell type is identified with a distinct cellular origin from monocytes, DCs and macrophages (green box), it is difficult to determine whether they should be incorporated into the MPS or not. This is because the current cells within the MPS are not develop-mentally linked and have no obvious functional property in common that would distinguish them from other immune cells. We suggest that transcriptional profiling could be used to determine whether any newly identified cell has important homology with monocytes, DCs or macrophages. This would open the possibility of incorporating a new cell type into the MPS. BATF3, basic leucine zipper transcriptional factor ATF-like 3; cDC1, classical type 1 DC; cDC2, classical type 2 DC; CDP, common DC precursor; HSC, haematopoietic stem cell; IRF4, interferon-regulatory factor 4.

Figure 2. Two levels of nomenclature for classifying mononuclear phagocytes

We suggest that mononuclear phagocytes should first be defined on the basis of their ontogeny (level one nomenclature; yellow boxes), followed by their function, location and/or morphology (level two nomenclature; blue boxes). This yields three main groups of cells — namely, common dendritic cell (DC) precursor (CDP)-derived DCs, embryonic-derived macrophages and monocyte-derived cells. We suggest that DCs should be further subdivided into ‘classical type 1 DCs (cDC1s)’, ‘cDC2s’ and plasmacytoid DCs (pDCs) because their development depends on distinct sets of transcription factors and because they arise from discrete committed precursors. In the lower part of the figure, we have added some examples to illustrate how our approach can yield a unifying nomenclature without losing flexibility. Level one nomenclature also includes unambiguous and widely accepted historical names (green box). Level two nomenclature can include surface markers that are used to identify the cells, the functional specialization studied or information on cell localization. Examples of level two nomenclature are provided, however, in many cases, level one should be sufficient to adequately define a population,, except when a novel function and/or relevant marker is required to discern a particular cell subset. We suggest the use of ‘MC’ as an abbreviation for monocyte-derived cells. However, this is not an officially accepted abbreviation and is incorporated here merely as a suggestion. BATF3, basic leucine zipper transcriptional factor ATF-like 3; cMoP, common monocyte progenitor; CSF1, colony-stimulating factor 1 (also known as M-CSF); CSF2, colony-stimulating factor 2 (also known as GM-CSF); FLT3, FMS-like tyrosine kinase 3; HSC, haematopoietic stem cell; IL-34, interleukin-34; iNOS, inducible nitric oxide synthase; IRF4, interferon-regulatory factor 4; RELMα, resistin-like molecule-α.