Trends in Immunology
Towards an understanding of the transcription factor network of dendritic cell development
Introduction
Research over the past several years has established a determining role of dendritic cells (DCs) in controlling the balance between immunity and immunological tolerance 1, 2. DCs originate from hematopoietic stem cells and occur in lymphoid and nonlymphoid tissues; they are particularly abundant in tissues that form an interface with the environment, such as the skin. DCs are specialized for uptake, transport, processing and presentation of antigens, and several DC subsets have been identified that differ in surface phenotype, function, activation state and anatomical location. There are three major DC populations: epidermal Langerhans cells (LCs), tissue/interstitial/dermal DCs (also referred to as ‘conventional’ DCs) and plasmacytoid DCs (pDCs) 1, 2, 3, 4.
Following antigen capture, DCs become activated and migrate to the lymphoid tissues, where they encounter T cells, to which they present the processed antigens in the context of MHC class I and II molecules. In the mouse, DCs in lymphoid tissues (spleen, thymus and lymph nodes) are subdivided into specific subsets based on selective expression of defining cell-surface molecules, such as CD4, CD8α, DEC205 (also known as CD205) and langerin (also known as CD207); for example, expression of langerin is characteristic of LCs. CD8α expression on DCs, initially used to distinguish ‘lymphoid’ and ‘myeloid’ DCs, is a useful marker for DC subset definition but does not define lineage origin.
Studies have revealed considerable plasticity in DC development, and DCs are now believed to originate from both lymphoid and myeloid precursors 1, 2, 3, 4, 5, 6, 7. Additionally, studies using genetically modified mice have added valuable information about the developmental pathways of DCs, and studies using knockout models, in which transcription factor genes have been deleted, have been particularly informative. We focus here on such studies.
Transcription factors are proteins that bind to specific sequence elements on DNA and regulate histone modification and chromatin structure [8]. Chromatin thereby acquires an active or silent state that regulates accessibility to components of RNA polymerase and gene transcription. Frequently, gene activity is determined by multiple and cooperating transcription factors, which form a complex network of transcriptional regulators that determine cell identity and cell fate. Thus, specific deletion of transcription factors by gene-knockout strategies has led to ablation of specific cell types, including DCs, and/or affected the balance of differentiation of different cell types such that specific DC subsets became predominant.
Stem cells and multipotent progenitor cells have a broad gene expression repertoire and promiscuously express genes of several hematopoietic lineages but at low levels 9, 10. During the development of the various hematopoietic lineages, including DCs, the gene expression repertoire and the options of stem cells and progenitor cells become increasingly restricted, leading to the establishment of a specific lineage from a choice of several. Such cell fate decisions are regulated by various signaling pathways, including cytokines and their receptors. These signaling pathways modulate the activity of genes encoding lineage-determining transcription factors that are central to lineage commitment and differentiation 10, 11. Several transcription factors have now been implicated in DC development and DC subset specification.
The currently prevailing model for hematopoiesis proposes the strict separation into common lymphoid progenitors (CLPs) and common myeloid progenitors (CMPs) as the first lineage commitment step in adult hematopoiesis [9]. However, recent findings question this model and suggest an alternative, that the first lineage restriction site is the separation of cells with erythroid/megakaryocytic potential from cells with a lymphomyeloid potential [12]. Thus, there might be further, as yet unidentified lineage restriction sites that also determine DC and DC subset development.
Section snippets
Transcription factors involved in early DC development
Ikaros is a member of the Krüppel family of zinc finger transcription factors, and studies of Ikaros dominant-negative (Ikaros DN−/−) and null mice (Ikaros−/−) demonstrated its major role in the development of all lymphoid lineages [13]. Ikaros DN−/− mice lack B and T lymphocytes, natural killer (NK) cells and both ‘conventional’ DC subsets (CD8α+ and CD8α− DCs) in spleen 13, 14 (Table 1; Figure 1). LCs and cells of the erythroid and myeloid lineages were unaffected 13, 14. The pool of c-kit+
Transcriptional regulators for pDC development
pDCs represent a distinct DC population in lymphoid tissues and peripheral blood and have a spherical plasmacytoid morphology. Following activation, these plasmacytoid cells acquire DC morphology, which is characterized by multiple cytoplasmic extensions 3, 4, 36. pDCs produce large amounts of interferon α (IFNα) when stimulated with bacterial DNA or by viral infection, and are therefore also referred to as natural IFN-producing cells (IPCs). In the mouse, pDCs express the B cell marker B220
Transcription factors in LC development
LCs, the cutaneous subset of DCs, are an immature sessile DC population in the epidermis and mucosal epithelia 1, 2, 3, 4, 53. LCs express the C type lectin langerin, which is also contained in LC-specific intracellular structures known as Birbeck granules. Although much is known about the activation and trafficking of LCs towards the cutaneous lymph nodes, the developmental origin of LCs and the factors involved are poorly understood.
In vitro culture systems of CD34+ cells from bone marrow or
Concluding remarks
In hematopoiesis, the development of lineage-specific cells, including DCs, involves a cascade of progenitors, each of which is more restricted to a specific cell fate than is its predecessor. Studies over the past ten years have identified signaling pathways, such as the Flt3–STAT3 and the TGFβ1 pathways, that have a major impact on DC development and lineage specification in vivo and in vitro. These signaling pathways regulate the activity of lineage-determining transcription factors, which
Acknowledgements
The authors thank colleagues and members of their group for helpful discussion and apologize to those colleagues whose publications were not cited as a result of space limitations. M.Z. and T.H. are supported by funds from the Interdisciplinary Center for Clinical Research ‘BIOMAT’ within the Faculty of Medicine at the RWTH Aachen University (VV B110-d and VV B112-a), Deutsche Forschungsgemeinschaft (DFG, Ze432.1 and Ze432.2) and the Bundesministerium für Bildung und Forschung (BMBF, 0311592A
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