Transcriptional regulation of dendritic cell diversity

Abstract

Dendritic cells (DCs) are specialized antigen presenting cells that are exquisitely adapted to sense pathogens and induce the development of adaptive immune responses. They form a complex network of phenotypically and functionally distinct subsets. Within this network, individual DC subsets display highly specific roles in local immunosurveillance, migration, and antigen presentation. This division of labor amongst DCs offers great potential to tune the immune response by harnessing subset-specific attributes of DCs in the clinical setting. Until recently, our understanding of DC subsets has been limited and paralleled by poor clinical translation and efficacy. We have now begun to unravel how different DC subsets develop within a complex multilayered system. These findings open up exciting possibilities for targeted manipulation of DC subsets. Furthermore, ground-breaking developments overcoming a major translational obstacle - identification of similar DC populations in mouse and man - now sets the stage for significant advances in the field. Here we explore the determinants that underpin cellular and transcriptional heterogeneity within the DC network, how these influence DC distribution and localization at steady-state, and the capacity of DCs to present antigens via direct or cross-presentation during pathogen infection.

Keywords: dendritic cells; differentiation; immunity; transcription factors.

Figure 1

Architecture of the DC network. The DC network is composed of multiple DC subsets that are broadly divided into cDCs, pDCs, MoDCs, and LCs which have distinct anatomical localizations in tissues. (A) Migratory DCs in peripheral tissues sample antigen from the periphery and then migrate through the lymphatic vessels to the afferent lymph node to present captured-processed antigens to the T cell within the T cell zone. In peripheral tissues, such as the skin, three main DC subsets are found. Dermal DCs are composed of the CD103⁺CD11b⁻ DC and CD11b⁺ DC. Both arise from a pre-DC that homed to the tissue. Under conditions of inflammation, some CD11b⁺ DC can be derived from a monocytic precursor. In addition to the dermal DCs, the epidermis of the skin is populated by the LCs which are derived from a Ly6C⁺ progenitor. (B) In secondary lymphoid tissues such as spleen, CD4⁺, CD8α⁺, and CD4⁻CD8α⁻ or double negative (DN) DCs are found. These subsets are also found in the draining lymph nodes which also receive the influx of the migratory CD11b⁺, CD103+CD11b⁻ DCs, and LCs arriving from the peripheral tissues.

Figure 2

Ontogeny of DC precursors. Short-term HSCs commit into multipotent progenitors that give rise to either a common-lymphoid progenitor (CLP) or a common myeloid progenitor (CMP). A population that lies downstream of CMP has been found to differentiate either into DC or macrophages, and was therefore named the macrophage-dendritic cell progenitor (MDP). Full commitment to the DC lineage is acquired at the CDP stage (common DC progenitor) where a CDP can either differentiate into plasmacytoid DCs (pDCs) or into a pre-DC. The latter will further differentiate into mature conventional DCs (cDCs) in the peripheral tissues, or secondary lymphoid organs.