Re(de)fining the dendritic cell lineage

Abstract

Dendritic cells (DCs) are essential mediators of innate and adaptive immune responses. Study of these critical cells has been complicated by their similarity to other hematopoietic lineages, particularly monocytes and macrophages. Progress has been made in three critical areas of DC biology: the characterization of lineage-restricted progenitors in the bone marrow, the identification of cytokines and transcription factors required during differentiation, and the development of genetic tools for the visualization and depletion of DCs in vivo. Collectively, these advances have clarified the nature of the DC lineage and have provided novel insights into their function during health and disease.

Figure 1. Development and migration of mononuclear phagocyte lineages in the steady state

Classical DCs (cDCs), plasmacytoid DCs (pDCs) and monocytes (Mono) derive from bone marrow (BM) progenitors. Macrophage-DC progenitors (MDPs) give rise to common dendritic cell progenitors (CDPs) and monocytes. CDPs differentiate into pDCs or committed precursors for cDCs (pre-cDCs). Pre-cDCs, pDCs, and monocytes transit through the blood and seed peripheral organs, where pre-cDCs complete their differentiation into CD8⁺/CD103⁺ or CD4⁺/CD11b⁺ cDCs. Monocytes can migrate into tissues and differentiate into macrophages. In the intestine, cDCs and macrophages populate the villi; cDCs are also present in intestinal lymphoid follicles (ILFs). In the skin, dermal DCs consist of both CD11b⁺ and CD103⁺ cDC subsets. Langerhans cells (LCs) populate the epidermis and self-renew locally. Macrophages, pDCs and both cDC subsets reside in the lung. A hallmark characteristic of cDCs is their ability to migrate upon antigen encounter from tissues to draining lymph nodes to prime T cell responses. In contrast, macrophages largely remain at the site of differentiation.

Figure 2. Global relationships between DC and macrophage subsets

Principal component analysis (PCA) of mature macrophage and DC subsets is shown. Each circle represents at least two microarray replicates. (a,b) Samples segregate by organ (PC1 and PC2) and by lineage (PC3). Genes with the greatest positive and negative loadings in PC3 reflect their DC- or macrophage-specific expression, respectively. Values in parentheses indicate proportion of variance explained. (c) Gene expression levels of Mafb and Zbtb46 in cDC and macrophage subsets are compared against PC3 scores from (b). MF, macrophage; PC, principal component; RPM, red pulp macrophage; SI, small intestine.

Figure 3. Distinguishing myeloid populations with lineage-specific transcription factors

(a) Lineage-specific transcription factor expression represents an alternative to surface marker-based methods for accurately identifying myeloid cell types. Lineage- or stage-specific transcription factors are indicated in colors corresponding to cell types in which they are uniquely expressed. For example, E2-2 expression distinguishes the pDC lineage while Zbtb46 distinguishes cDCs. (b) Shown is the theoretical heterogeneity within progenitor stages as defined by FACS (dashed circles). For example, cells characterized as CDPs using cell surface markers include a subpopulation of cells already committed to the cDC lineage, which are identified by expression of Zbtb46.

Figure 4. Stage-specific expression of transcription factors controlling DC development and specialization

(a) Shown are approximate mRNA expression levels^,, of selected transcription factors regulating DC development. Factors are grouped by the lineage in which they are required. Vertical bars indicate the stage at which each factor is essential for development. (b) Shown are sequential transcription factor requirements during development. Analysis of models deficient in these factors suggests that an important consequence of subset specialization is the ability to respond differentially to pathogen challenge through the secretion of specific cytokines. This specificity closely resembles the cytokine requirements for CD4⁺ T helper (T_H) subset differentiation, highlighting that DC responses are a key determinant of the resulting adaptive immune response. As in T cells, DCs may be better characterized by function rather than surface marker expression, i.e. CD8⁺ cDCs as “DC12” cells.