ReviewSystems immunology allows a new view on human dendritic cells
Introduction
In 2014, Guilliams et al. suggested a new nomenclature for dendritic cells (DCs), monocytes, and macrophages as members of the mononuclear phagocyte system [1]. They proposed to define the different cell lineages primarily based on ontogeny followed by location, function, and phenotype. In contrast, the first description of murine DCs by Ralph Steinman in 1973 was entirely focused on the morphological characteristics and the location of these exciting cells [2], followed by two consecutive publications on the in vitro [3] and in vivo [4] functions of DCs. DCs were shown to effectively present antigen via MHC molecules to T cell receptors, thereby even activating naïve T cells [5]. As for any other immune cell, with the advent of flow cytometry, the search for DC-specific cell markers was initiated and numerous genes have been suggested as DC-specific [6]. Until recently, murine DCs were characterized to express high levels of MHC class II molecules and CD11c [6] while human DCs are highly expressing HLA-DR but only some subsets express CD11c [1,6]. Further exploitation using numerous other cell surface markers suggested significant heterogeneity within the DC compartment [[6], [7], [8], [9], [10]] with sometimes even conflicting results concerning the functionality of certain cell subsets [11,12]. Nevertheless, both in the murine and the human system, the DC compartment could be divided up in several independent subsets including plasmacytoid DCs (pDCs) and conventional or classical DCs (cDCs) with two further subsets, cDC1 and cDC2 [1,6] (see also Fig. 1). Mainly established in the murine system, DC subsets were shown to derive from a common dendritic cell precursor (CDP), which further differentiates into either a pre-pDC as the precursor for pDC or an early precursor of cDCs, called early pre-cDC [13]. This early pre-cDC further differentiates into either pre-cDC1 or pre-cDC2, which are the respective precursors for cDC1 and cDC2s [13]. While the murine system is well suited for cell ontogeny studies, the precursor landscape of human DCs was rather obscure until recently [14]. In fact, for a long time, it was postulated that human DCs are derived directly from monocytes [[15], [16], [17]].
In 1994, Sallusto and Lanzavecchia introduced an in vitro culture system of human monocyte-derived DCs (moDCs), which revolutionized subsequent studies into human DC biology [16] laying also the ground for the development of DC vaccines [18]. MoDCs show many of the characteristics of ex vivo isolated human DCs including phenotype, morphology, and function [6]. Yet, with the advent of genomic technologies, particularly global assessment of transcriptional regulation, it became more and more evident that moDCs show differences to their in vivo counterparts. Whether this is solely due to in vitro culture conditions or whether these cells have – yet unrecognized – in vivo counterparts remains unresolved.
Clearly, systems immunology approaches, integrating computational modelling based on high throughput data with the assessment of classical parameters describing morphology, phenotype, and function of DCs, opens completely new avenues to better characterize the human DC compartment, particularly since experimental settings possible in murine model systems (fate mapping, genetic engineering for research), will never be available. Furthermore, the development of novel genomic technologies allowing the assessment of transcriptomes on the single cell level have already revolutionized our knowledge of murine DCs [[19], [20], [21], [22]].
A detailed outline of an integrated functional system of DCs and monocyte-derived cells as well as the distinct pDC system has been recently reviewed elsewhere [6,23], and we refer the reader to these publications for further information. Here, we will focus on the most recent developments in human DC biology. Indeed, systems immunology approaches have revealed the relationship of different human DC subsets throughout hematopoietic and non-hematopoietic tissues and organs [24,25]. Single cell RNA-sequencing (scRNA-seq) combined with mass cytometry (CyTOF) and assessment of classical parameters was instrumental to map the human DC lineage [14]. Lastly, systems approaches unequivocally revealed that moDCs are closely related to inflammatory myeloid cells in vivo, but not to in vivo DCs under homeostatic conditions ([26] and own published results).
Section snippets
Human dendritic cells in lymphoid tissues
Based on many studies performed during the last two decades, a consensus of the cell population structure within the human DC compartment has been established. In lymphoid – but also non-lymphoid – tissues, two main groups, namely plasmacytoid DCs (pDCs) and classical or myeloid DCs (cDCs) are recognized. Based on phenotypic and functional characterization, myeloid DCs have been further subdivided into two subsets: What is now known as the human cDC1 population was defined by the expression of
Human dendritic cells in non-lymphoid tissues
DC populations in non-lymphoid tissues had long been thought to be far less heterogeneic. Yet, more detailed multi-parameter flow cytometry analyses in recent years - particularly in the murine system - led to the identification of several newly defined subsets based upon surface marker expression suggested to be unique identifiers [7]. In 2010, Guilliams et al. proposed a unifying classification across tissues and species defining five major DC subsets [42] which resemble the currently used
Single cell analysis of human dendritic cells
Single cell RNA-sequencing is currently revolutionizing our understanding of the cell as the basic unit of any multi-cellular organism [[65], [66], [67], [68], [69], [70], [71], [72], [73], [74], [75]]. While such studies are more easily performed in animal models, the mapping of human cells on the single cell level applying sequencing technologies is more challenging. This is particularly true for tissues that are not easily obtained from healthy individuals or even patient biopsies. Not
Ontogeny of human dendritic cells
During haematopoiesis, that takes place within the bone marrow, stem cells give rise to progenitor cells that consequently differentiate into more specialized subtypes. Single cell-based analysis of murine bone marrow revealed a continuous development of distinct transcriptionally primed progenitor populations from an early precursor [77] suggesting that previously described distinct intermediates (e.g. CMPs, GMPs) are heterogenous albeit individual cells are already predetermined towards a
Functional studies of newly defined human DC subsets
Recent studies have started to address functional analyses of the now defined DC subsets. Harnessing an organ donor tissue resource, DC subsets were analysed in various tissues from nearly 80 individuals covering an age range from less than 1–93 years [84]. cDC1 and cDC2 subsets were found to be tissue-specifically distributed and, as this was conserved between the various donors, found to be retained over life. cDC2s were a common feature of draining lymph nodes with the highest prevalence in
What are monocyte-derived human dendritic cells?
Although it is now rather clear that tissue macrophages and dendritic cells are not derived from monocytes, blood monocytes can enter tissues and get reprogrammed when doing so, particularly under inflammatory conditions [88]. During this progress monocytes can gain many properties associated with either tissue macrophages or dendritic cells. According to a marker-based nomenclature, human blood monocytes have been subdivided into CD14+CD16− classical, CD14+CD16+ intermediate and CD14loCD16+
Conclusions and future directions
The application of systems immunology approaches in the last five to seven years has been critical to delineate the human dendritic cell system. The historical characterization of cell populations based on known cell surface markers has proven to be insufficient for a comprehensive functional discrimination of distinct cell subsets, especially with respect to the definition of progenitor populations. In contrast, an unsupervised analysis of conventional multi-colour flow cytometry, CyTOF, bulk
Funding sources
This work was supported by the German Research Foundation (DFG) to JLS (SFB704, Excellence Cluster ImmunoSensation).
Acknowledgements
JLS is a member of the Excellence Cluster ImmunoSensation.
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