Key Points
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Definition of the developmental origin and precursors of dendritic cells (DCs) is essential to assess whether DC functional diversity results from the existence of developmentally independent DC subpopulations or from environmentally regulated acquisition of specific functions by DC subsets that share a common differentiation origin.
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Defining the origin of DCs will help us to understand the induction and control of immunity by DCs, as well as the use of DCs for immunotherapy.
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New data on the origin and differentiation of DCs depend on a large diversity of experimental approaches including in vivo DC reconstitution experiments, analysis of genetically deficient mice, in vitro DC differentiation assays and studies of the recruitment of DC precursors and DC differentiation during microbial infections.
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The concept that mouse CD8− and CD8+ DCs correspond to myeloid and lymphoid DCs, respectively, has been proven to be incorrect, as both subsets can be generated by either lymphoid- or myeloid-committed progenitors.
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However, neither the proposed lymphoid origin for plasmacytoid DCs nor the existence of a developmentally restricted lymphoid DC subset have been formally shown, so far.
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The description of a population of DC precursors in mice that can generate CD8− and CD8+ DCs, as well as B220+ plasmacytoid CDs, supports the hypothesis that all DC subsets are derived from a single DC common progenitor.
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New data support the concept that induction of T-cell immunity against microbial infections involves the recruitment of DC precursors to lymphoid tissues and their local differentiation into DCs.
Abstract
Functional specialization allows defined dendritic-cell (DC) subsets to induce efficient defence mechanisms against pathogens and tumour cells, and maintain T-cell tolerance by inducing the inactivation of autoreactive T cells. A crucial question, which has important implications for both our understanding of the induction and control of immunity by DCs, as well as the use of DCs for immunotherapy, is whether the functional diversity of DCs results from the existence of developmentally independent DC subpopulations, or whether DC subsets that share a common differentiation origin acquire specific functions in response to environmental signals. This review discusses recent findings on mouse DC development.
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Acknowledgements
I would like to thank G. Martínez del Hoyo, V. Parrillas, M. López-Bravo and B. León for critical reading of this manuscript and help in its preparation, and K. Shortman, M. Zenke, M. Luisa Toribio and A. Corbí for helpful discussions. Our studies were funded by the European Commission, the Community of Madrid, Spain and the Ministry of Science and Technology of Spain.
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Glossary
- DC RECONSTITUTION ASSAYS
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Assays that allow the in vivo analysis of the differentiation potential of different precursor populations after transfer into irradiated recipients; the precursor progeny is subsequently studied by using a genetic marker that allows the detection of cells from donor or recipient origin.
- BROMODEOXYURIDINE INCORPORATION ASSAY
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(BrdU). An assay in which BrdU, a thymidine analogue, is incorporated into DNA during DNA replication. Cells that have incorporated BrdU, and presumably have divided, are then visualized using fluorescence-labelled BrdU-specific antibodies followed by flow cytometry.
- PLASMACYTOID DCS
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A subset of immature dendritic cells (DCs), originally described in humans, that are characterized by their capacity to produce high levels of type I interferon after stimulation with virus. They can differentiate into potent antigen-presenting cells after activation.
- COLONY-FORMING UNIT EXPERIMENTS
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These experiments address the differentiation capacity of haematopoietic precursors, by analysing the cell colonies that result from the proliferation and differentiation of single precursor cells, using in vivo transfer techniques or cell-culture systems.
- COMMON LYMPHOID PROGENITORS
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Bone-marrow clonogenic precursors that are committed to the lymphoid lineage, generating T cells, B cells and natural killer cells, but are devoid of myeloid differentiation potential.
- COMMON MYELOID PROGENITORS
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Bone-marrow clonogenic precursors that are committed to the myeloid lineage and give rise to megakaryocyte–erythrocyte or granulocyte–macrophage progenitors, but are devoid of lymphoid differentiation potential.
- DC MATURATION
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A process resulting from the engagement of activation receptors on dendritic cells (DCs), such as Fc receptors, Toll-like receptors, cytokine receptors or CD40, which involves the upregulation of MHC molecules and co-stimulatory molecules and the acquisition of specific functions that enable DCs to activate T cells efficiently.
- DC PRECURSORS
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(Pre-DCs). A population of dendritic cell (DC)-committed precursors present in mouse blood that can fully reconstitute the CD8−, CD8+ and plasmacytoid B220+ DC subpopulations after transfer into irradiated recipients51. Precursor DCs are CD11c+ B220+CD11b+ CD43+CD44+ CD62L+ FcRγ+MHC class II−CD19−CD40−CD86−c-kit− IL-7Rα−IL-3Rα−DEC205− F4/80−Gr1−.
- CROSS-PRIMING
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A mechanism by which an antigen-presenting cell processes exogenous cell-associated antigens and presents them in the context of MHC class I molecules, leading to the activation of antigen-specific CD8+ T cells.
- DANGER SIGNALS
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Cell-wall components and other products of pathogens that alert the innate immune system to the presence of potentially harmful invaders, usually by interacting with Toll-like receptors and other pattern recognition receptors expressed by tissue cells and dendritic cells, for example.
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Ardavín, C. Origin, precursors and differentiation of mouse dendritic cells. Nat Rev Immunol 3, 582–591 (2003). https://doi.org/10.1038/nri1127
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DOI: https://doi.org/10.1038/nri1127
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