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  • Review Article
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Steady-state and inflammatory dendritic-cell development

Key Points

  • The functionally specialized subtypes of dendritic cells (DCs) are the products of different branches or sub-branches of haematopoietic pathways, which involve different immediate precursor cells. Regulating each pathway involves different cytokines and different transcription factors.

  • There is remarkable developmental flexibility at the earlier stages of haematopoiesis, with both myeloid- and lymphoid-biased precursor cells potentially able to produce all DC subtypes, providing that they express the cytokine receptor FLT3 (FMS-related tyrosine kinase 3). Precursors that are committed to particular DC subtypes are found downstream of these early precursor cells.

  • There is a clear distinction between the DCs found in steady state and those found in lymphoid organs as a consequence of inflammation. Inflammatory DCs are produced from inflammatory monocytes, and this might be modelled in culture by the production of DCs from monocytes that are stimulated with the cytokine GM-CSF (granulocyte/macrophage colony-stimulating factor).

  • The migratory DCs, such as Langerhans cells and interstitial DCs, which migrate to the lymph nodes from peripheral tissues through lymph vessels, might also be of monocyte origin. Monocytes can regenerate Langerhans cells in the epidermis following inflammation-induced depletion, and this depends on the cytokine M-CSF (macrophage colony-stimulating factor).

  • The generation of non-migratory, lymphoid-tissue-resident conventional DCs, such as those in the spleen, depends on the cytokine FLT3L (FLT3 ligand). The immediate precursor is DC committed, is not a monocyte and is found in the lymphoid tissue itself. Upstream precursors of these DCs can be found in the bone marrow. One such intermediate precursor can generate macrophages as well as conventional DCs, but not plasmacytoid DCs or granulocytes.

  • The generation of interferon-producing plasmacytoid DCs also depends on FLT3L, but takes place in the bone marrow and branches off at an intermediate precursor stage from the pathway that produces conventional DCs. The plasmacytoid cells produced in the bone marrow then reach lymphoid tissues through the bloodstream. A subset of the plasmacytoid cells found in spleen and thymus have developed through a lymphoid-related pathway that involves the activation of many genes that are involved in B-cell development.

Abstract

The developmental pathways that lead to the production of antigen-presenting dendritic cells (DCs) are beginning to be understood. These are the last of the pathways of haematopoiesis to be mapped. The existence of many specialized subtypes of DC has complicated this endeavour, as has the need to distinguish the DCs formed in steady state from those produced during an inflammatory response. Here we review studies that lead to the concept that different types of DC develop through different branches of haematopoietic pathways that involve different immediate precursor cells. Furthermore, these studies show that many individual tissues generate their own DCs locally, from a reservoir of immediate DC precursors, rather than depending on a continuous flux of DCs from the bone marrow.

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Figure 1: Dendritic-cell development from haematopoietic precursors.
Figure 2: Model for the retention of macrophage and dendritic-cell potential during haematopoiesis.
Figure 3: Pathways to splenic dendritic cells.
Figure 4: The regeneration of Langerhans cells.

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Acknowledgements

We are grateful to all our colleagues, in particular L. Wu, for discussion and advice, and K. McIntosh for assistance with the manuscript. We are supported by the National Health and Medical Research Council, Australia.

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FURTHER INFORMATION

Distinct precursors of the dendritic cell subtypes

Glossary

T-cell tolerance

The selective inactivation of T cells that are responsive to particular antigens by deleting such T cells, by paralysing them to produce a state of anergy, or by generating regulatory T cells that restrict their activity. The last two effects can occur concomitantly.

Mucosal tissues

The mucus-covered moist tissues where the body exchanges gases or nutrients with the external environment. These include the nose, mouth, lungs, gut and reproductive tract.

Steady state

The state of the immune system in healthy adult mice that are not subject to infections or inflammatory stimuli.

Danger signals

Agents that alert and activate the innate and adaptive immune systems and initiate immune responses. Danger signals can be associated with microbial invaders (exogenous danger signals) or can be produced by damaged cells (endogenous danger signals).

Type I interferons

These are rapidly induced by virus replication as well as by some bacterial infections. They immediately limit viral replication, as well as enhancing later antigen-specific immune responses.

Immunoglobulin heavy-chain (IgH) gene D–J rearrangements

The immense diversity of antibodies is achieved by a process of somatic rearrangement of immunoglobulin genes. This occurs as lymphoid cells develop. The process begins on the IgH genes, with rearrangements at the D (diversity) and J (joining) regions occurring before those involving the V (variable) regions. Because of the close developmental relationship between T and B cells, some of the IgH genes in T cells acquire D–J rearrangements before T-cell development branches off from B-cell development.

Bromodeoxyuridine

(BrdU). A thymidine analogue that can be incorporated into DNA during DNA replication. Treatment with BrdU can allow the detection of cells that are dividing or have divided, by intracellular staining with fluorescence-labelled BrdU-specific antibodies followed by flow cytometry.

Parabiotic mice

Pairs of mice that are surgically joined by cutaneous vascular anastomosis, so that they have a common blood circulation while maintaining separate organs and tissues.

γc

A type I cytokine receptor chain that is shared by the receptors for the interleukins IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21.

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Shortman, K., Naik, S. Steady-state and inflammatory dendritic-cell development. Nat Rev Immunol 7, 19–30 (2007). https://doi.org/10.1038/nri1996

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