Decoding the Heterogeneity of Human Dendritic Cell Subsets

Abstract

Dendritic cells (DCs) have been classified into distinct subsets based on phenotype and ontogeny. In the past few years, high throughput single-cell approaches have revealed further heterogeneity of human DCs, in particular at the transcriptomic level. Herein examined, are recent studies describing new human DC populations based on single-cell RNA-seq analysis, and a unified view of these emerging DC populations is presented. Also assessed are the features that define bona fide DC lineages, as opposed to cell states of the same lineage. Finally, where these newly described DC populations fit in the ontogeny-based classification of human DCs is examined. Key Features Defining DC Subsets DCs (see Glossary) are recognized as the most efficient antigen-presenting cells, and are present throughout the mammalian body in both lymphoid organs and peripheral tissues. Since the initial identification of DCs in mouse spleen by Ralph Steinman [1], methodological advances have gradually revealed the complexity of DC populations. Multi-color flow cytometry has shown the existence of several subpopulations of DCs displaying distinct surface phenotypes [2]. Transgenic mouse models have revealed the transcriptional control of DC lineages and specific functions of DC subsets [3]. Transcriptomic analyses have also evidenced a conserved gene expression profile for each DC subset across tissues and species [4,5]. The current classification of DC subsets is based on their cellular and molecular ontogeny: (i) plasmacytoid DCs (pDC); (ii) type 1 classical DCs (cDC1); (iii) type 2 classical DCs (cDC2); and (iv) monocyte-derived DCs (mo-DC) [6] (Table 1). To better understand the biology of human immune cells, an increasing number of groups are analyzing immune cells, including DCs, directly purified from human tissues using high-dimensional single-cell approaches. These single-cell analyses have revealed further heterogeneity within human DC subsets, especially at the transcriptional level (Table 2). However, in this rapidly evolving field, there is still little consensus on the identification and naming of new DC populations. In this Opinion article, the aim is to provide a unified view of the newly described human DC populations, and to discuss the limitations of single-cell RNA sequencing (scRNA-seq) for identifying DC subsets. It is argued, that differential gene expression profiles are not sufficient to distinguish bona fide DC lineages from cell states of the same lineage. Finally examined, are the place of these newly described DC populations in the widely used ontogeny-based DC classification. Transcriptional Heterogeneity of Human DCs Revealed by Single-Cell Approaches DCs orchestrate immune responses, and manipulating their properties holds great promise for therapeutic strategies to treat chronic inflammatory diseases, cancers, graft rejection, or to improve vaccine efficiency [7-9]. DC dysfunction may also play a crucial part in autoimmune diseases. Because each DC subset displays unique functions [3], it is vital to understa...

Development of an Inflammatory CD14+ Dendritic Cell Subset in Humanized Mice

“…We showed that CD14 + CD1c + cells as well as other cDCs, primed and promoted the proliferation of naïve CD4 + T cells at higher levels than did monocytes (Figure 2C), supporting a distinct functionality of CD14 + CD1c + cells from macrophages. Moreover, it is difficult to distinguish between DC3s and MoDCs because their functionality and transcription profiles tend to overlap conspicuously and no discriminative markers have been reported yet (13). However, our transcriptional analysis demonstrated that CD14 + CD1c + cells isolated from hNOJ mice are closer to cDC2s and DC3s than to MoDCs in humans (Supplementary Figure 4).…”

“…However, differences in phenotypes and functionalities exist in the same DC subsets between humans and mice (8)(9)(10)(11)(12). Furthermore, there is a new DC subset in humans, DC3s, whose equivalent counterparts have not yet been identified in mice (13). Thus, it is valuable to establish animal models that precisely reproduce human DC subsets, as they can prove useful for translational research where DCs are utilized for immunotherapy against cancer and infectious diseases (14)(15)(16).…”

High-dimensional profiling demonstrates complexity, tissue imprinting, and lineage-specific precursors within the mononuclear phagocyte compartment of the human intestine

“…Thus, characterising these populations and understanding their functions under different conditions will be important for improving the treatment of disease and for developing preventative strategies, such as vaccines. However, this has proved difficult due to the expression of overlapping phenotypic markers and due to the heterogeneity within each subset, which is becoming increasingly evident (Brown et al, 2019; Dutertre et al, 2019; Guilliams et al, 2016; Villar and Segura, 2020). This is particularly so in non-lymphoid tissues such as the intestine, where local factors imprint unique adaptations and functions, meaning that each tissue has to be explored independently and at the single-cell level (Blériot et al, 2020).…”

The Interplay between the Immune and the Endocannabinoid Systems in Cancer

“…Dendritic cells ( DCs ). DCs are a diverse group of specialized antigen-presenting cells (APCs) playing a central role in inducing primary immune responses, immunological tolerance and ensuring the regulation of responses of T cells [ 248 ]. Although DCs constitute a rare immune cell population within tumors and lymphoid organs, these cells are central to initiation and tumor immunity [ 249 ].…”