The dendritic cell lineage: ontogeny and function of dendritic cells and their subsets in the steady state and the inflamed setting

Abstract

Dendritic cells (DCs) form a remarkable cellular network that shapes adaptive immune responses according to peripheral cues. After four decades of research, we now know that DCs arise from a hematopoietic lineage distinct from other leukocytes, establishing the DC system as a unique hematopoietic branch. Recent work has also established that tissue DCs consist of developmentally and functionally distinct subsets that differentially regulate T lymphocyte function. This review discusses major advances in our understanding of the regulation of DC lineage commitment, differentiation, diversification, and function in situ.

Figure 1

Heat map representation of transcripts differentially expressed in progenitor and differentiated DCs. (a) Heat map representation of pathogen-recognition receptors (PRRs) and antigen receptors, cytokine and cytokine receptors, and chemokines and chemokine receptors in common myeloid progenitors (CMPs), granulocyte macrophage progenitors (GMPs), macrophage DC progenitors (MDPs), common DC progenitors (CDPs), and CD8⁺ spleen pDCs, CD8⁺ spleen cDCs, CD103⁺CD11b⁻ lamina propria cDCs, CD4⁺ spleen cDCs, CD103⁺CD11b⁺ lamina propria DCs, CD103⁻ CD11b⁺ lamina propria cDCs, epidermal Langerhans cells (LCs), red pulp macrophages (MFs), and blood monocytes. Red represents high and blue represents low relative expression. (b) Principal components analysis (PCA) of 15% of the most variable transcripts expressed by lymphoid tissue CD8⁺ cDCs, lymphoid tissue CD8⁻ cDCs, nonlymphoid tissue CD103⁺ cDCs, nonlymphoid tissue CD11b⁺ cDCs, epidermal LCs, monocytes, and MF populations provides a visual representation of the heterogeneity of the mononuclear phagocytic lineage. cDC and MF populations cluster distinctly on opposite sides of the PCA, whereas the CD11b⁺ cDC distribution throughout the PCA suggests that these cells are more heterogeneous. Intriguingly, the CD11c subcapsular MF population clusters near DCs, suggesting that this population is more closely related to DCs than to macrophages (which is further suggested by the expression of zbtb46). (Additional abbreviations used in figure: MLN, mesenteric lymph node; SI, small intestine; SLN, skin-draining lymph node.)

Figure 2

Phenotypes of murine DC progenitors. The illustration on the left suggests that the granulocyte macrophage progenitor (GMP) expresses high levels of c-kit and low levels of CX₃CR1, Csf-1R (CD115), and Flt3 (CD135), whereas the macrophage DC progenitor (MDP) is positive for c-kit, CX₃CR1, Csf-1R (CD115), and Flt3 (CD135). The common DC progenitor (CDP) expresses intermediate levels of c-kit and is positive for CX₃CR1, Csf-1R (CD115), and Flt3 (CD135); pre-cDCs express no or low levels of c-kit but express CD115 and high levels of CD135. The table at the right summarizes the detailed phenotype of MDPs, CDPs, and pre-cDCs.

Figure 3

Transcriptional control of DC commitment and differentiation. The illustration depicts a heat map representation of cytokines, TLRs, and some transcription factors expressed along the myeloid lineage, starting from the common myeloid progenitors (CMPs), to the granulocyte macrophage progenitors (GMPs), macrophage DC progenitors (MDPs), common DC progenitors (CDPs), pre-cDCs (circulating cDC progenitors), monocytes, plasmacytoid DCs (pDCs), and lymphoid tissue–resident CD8⁺ and CD11b⁺ cDCs.

Figure 4

Regulation of DC development and homeostasis in mice. This illustration summarizes the current model of the developmental pathways of both lymphoid tissue–resident and nonlymphoid tissue–resident murine DCs. Dashed lines indicate pathways that are likely but not yet definitively shown to operate in DC development. Cytokines and transcription factors that are important in each transition are indicated (HSC, hematopoietic stem cell; CMP, common myeloid progenitor; CLP, common lymphoid progenitor; MDP, macrophage DC progenitor; CDP, common DC progenitor; ETP, early thymic progenitor; mono, monocyte; LC, Langerhans cell).

Figure 5

DC controllers of adaptive immunity. This illustration summarizes key DC functions, highlighting their importance as regulators of adaptive immune functions in lymphoid and nonlymphoid tissues. DC subsets that populate peripheral tissues capture commensals, food antigens, or exogenous antigens and migrate in a CCR7-dependent manner to the draining lymph node, where they present tissue-derived antigens to CD8⁺ T cells (cross-presentation) and CD4⁺ T cells (direct presentation), thereby inducing peripheral tolerance in the steady state or effector immunity in the injured state. Gut tissue CD103⁺ cDCs that migrate to the draining lymph node can promote the induction of gut-homing molecules (α4β7 and CCR9) on naive T cells (tissue imprinting), thereby promoting T cell migration to gut tissue. cDCs also promote T cell–dependent class switch recombination (CSR).

Figure 6

Phenotype of human DC subsets. This figure summarizes the phenotype and pathogen receptor expression profile location of human DC subsets known so far as well as the putative mouse DC subset equivalent. Abbreviations: LC, Langerhans cells; ND, not determined; PRRs, pattern-recognition receptors.