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  • Review Article
  • Published:

Dendritic cell migration in health and disease

Nature Reviews Immunology volume 17, pages 30–48 (2017)Cite this article

Subjects

Key Points

  • During embryonic development and postnatally, dendritic cell (DC) progenitors migrate into non-lymphoid organs and differentiate into immature DCs.

  • Immature DCs form a dense network of sentinel cells at all outer and inner surfaces of the body, as well as in most organs.

  • Immature DCs sample and process both self and foreign antigens. They subsequently undergo an activation process that is triggered by either an 'intrinsic programme' or in response to the recognition of molecular patterns associated with pathogens and the microbiota.

  • As part of the activation programme, DCs upregulate CC-chemokine receptor 7 (CCR7) and increase their motility. The CCR7 ligand CC-chemokine ligand 21 (CCL21) is expressed on terminal lymphatics and CCR7–CCL21 interactions enable DCs to enter the lymphatic vasculature and eventually the draining lymph node, where they migrate into the T cell-rich paracortex.

  • Within lymph nodes and other lymphoid organs, DCs present antigen to T cells, leading either to the induction of immunological tolerance or to the expansion of protective pro-inflammatory effector and memory T cell populations. In some cases, DC-mediated presentation of self or harmless foreign antigens leads to the formation of effector T cell populations; as such, DCs can contribute to the development of autoimmune or allergic diseases.

  • Effector T cells that develop during protective immune responses home to the tissue site of infection and inflammation and frequently contribute to the recruitment of further DC progenitors. Following their differentiation, such progenitors can present antigen to T cells, either locally or — after mobilization — in draining lymph nodes, thus amplifying protective as well as detrimental immune responses.

Abstract

Dendritic cells (DCs) are potent and versatile antigen-presenting cells, and their ability to migrate is key for the initiation of protective pro-inflammatory as well as tolerogenic immune responses. Recent comprehensive studies have highlighted the importance of DC migration in the maintenance of immune surveillance and tissue homeostasis, and also in the pathogenesis of a range of diseases. In this Review, we summarize the anatomical, cellular and molecular factors that regulate the migration of different DC subsets in health and disease. In particular, we focus on new insights concerning the role of migratory DCs in the pathogenesis of diseases of the skin, intestine, lung, and brain, as well as in autoimmunity and atherosclerosis.

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Figure 1: Overview of dendritic cell migration routes.
Figure 2: Trafficking of intestinal antigen-presenting cells.
Figure 3: Antigen drainage and DC migration routes in the CNS.

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Acknowledgements

The work of R.F. is funded by grants of the European Research Council (ERC advanced grant 322645-LYMPHATICS-HOMING), the Deutsche Forschungsgemeinschaft, DFG (SFB900-B1, SFB738-B5, Fo334/2-2, Fo334/5-1) and the State of Lower Saxony (Niedersachsen Research Network on Neuroinfectiology,N-RENNT; and BIOFABRICATION for NIFE).

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Author notes

  1. Tim Worbs and Swantje I. Hammerschmidt: These authors contributed equally to this work.

Authors and Affiliations

  1. Institute of Immunology, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625, Hannover, Germany

    Tim Worbs, Swantje I. Hammerschmidt & Reinhold Förster

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  1. Tim Worbs
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  2. Swantje I. Hammerschmidt
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Correspondence to Reinhold Förster.

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PowerPoint slides

Glossary

Mononuclear phagocyte system

(MPS). The term coined by Van Furth in 1968 comprises myeloid immune cells other than polymorphonuclear granulocytes and initially included monocytes and macrophages, and, following their discovery, dendritic cells.

Plasmacytoid DCs

(pDCs). Initially described as innate immune cells capable of producing large amounts of type I interferons in response to viral stimuli.

Haptotaxis

A persistent directional migration along gradients of a chemoattractant that are immobilized on cells and/or elements of the extracellular matrix, in contrast to classical chemotaxis, which develops in response to gradients in a soluble phase.

Subcapsular sinus

The entry side of the lymph node that is close to the afferent lymph vessels. The ceiling and the floor of the sinus are lined by lymphatic endothelial cells.

Lymph node paracortex

The area of the lymph node between the subcapsular cortex and the medullary cords. The paracortex is a DC- and T cell-rich area with high endothelial venules, where circulating lymphocytes leave the bloodstream to enter the lymph node.

Langerhans cells

(LCs). These epidermal cells are regarded as a DC–macrophage hybrid, as they exhibit characteristics of both types of phagocytes. They are highly migratory, efficiently reaching skin-draining lymph nodes, but are unique among DC subsets in that they arise from embryonic progenitors and are radio-resistant, long-lived and develop independently of FLT3 ligand.

Conventional DC1s

(cDC1s). Subset of conventional DCs that in the mouse comprises CD8α+ DCs in lymphoid organs, as well as CD103+ DCs in non-lymphoid tissues. Importantly, in both, human and mice, cDC1s express the markers XCR1, CLEC9A, and CADM1, and display a developmental dependency on ID2, IRF8, NFIL3, and members of the AP1 transcription factor family, namely BATF, BATF2 and BATF3.

Conventional DC2s

(cDC2s). Subset of conventional DCs that in both, human and mice, is characterized by the expression of CD11b and SIRPα/CD172a while lacking XCR1 and CLEC9A. Transcription factors required for their development include IRF4, NOTCH2, PU.1, RELB, and RBPJ, with the exact combination being in part tissue-dependent.

Double negative cDCs

(DN cDCs). A subset of conventional DCs in the mouse that does not express CD103 or CD11b.

Yolk sac-derived erythro-myeloid progenitor

Progenitor cells that develop in the yolk sac (a membranous sac attached to the embryo) colonize the nascent fetal liver and give rise in a first wave of haematopoiesis to fetal erythrocytes, macrophages, granulocytes and monocytes.

Peripheral tolerance

Central tolerance mechanisms do not eliminate all self-reactive lymphocytes, in part because food antigens and some self-antigens are not presented in the thymus, the site of T cell development. Therefore, peripheral tolerance mechanisms control lymphocytes that first encounter their cognate self-antigens outside of the thymus. These mechanisms include anergy and deletion of self-reactive T cells as well as suppression of autoreactive cells by regulatory T cells.

Contact hypersensitivity

Experimental animal model for human allergic contact dermatitis. Upon painting a hapten onto the skin, skin DCs migrate to the lymph nodes where they activate hapten-specific T cells. Re-exposure to the same hapten results in the recruitment of specific T cells to the dermis, which triggers the inflammatory process that is responsible for the cutaneous lesion. Contact hypersensitivity and allergic contact dermatitis are examples of type IV hypersensitivity reactions (T cell-mediated allergic reactions).

Cross-presentation

The ability to present extracellular antigens on MHCI molecules to CD8+ T cells. It is required for triggering immune responses against viruses that do not infect antigen-presenting cells.

Resolvin E1

An endogenous anti-inflammatory lipid mediator biosynthesized from the ω-3 polyunsaturated fatty acid eicosapentaenoic acid during the resolution phase of acute inflammation. Also binding to the chemokine-like receptor CMKLR1, it attenuates inflammation in several disease models, including peritonitis, polymicrobial sepsis and allergic airway inflammation.

Amoeboid migration

Mode of rapid motility that is driven by actin-rich pseudopods, hydrostatically generated blebs and a highly contractile uropod. It is characterized by weak or absent adhesion and little or no extracellular matrix proteolysis. DCs, lymphocytes, and cancer cells exhibit amoeboid motility.

Immune privilege

The observation that foreign antigens and allografts introduced into certain sites of the body do not (or do so only very slowly) elicit (cellular) adaptive immune reactions. These sites include the CNS, eyes, testicles, placenta and fetus. However, at least for the CNS, the idea of an 'absolute' immune privilege is no longer valid, as immune surveillance of the CNS does occur within certain limitations.

Blood–brain barrier

Owing to the specialized composition of the so-called neurovascular unit (comprising endothelial cells, pericyte, and astrocyte endfeet) the permeability of blood vessels for plasma components, blood cells and pathogens is much lower in the brain than in other organs. Endothelial cells of CNS blood vessels express particularly high levels of tight junction proteins as well as of substrate-selective transporters. Importantly, some regions of the CNS, including the so-called circumventricular organs, contain 'leaky' blood vessels and are not part of the brain side of the blood–brain barrier.

Rostral migratory stream

(RMS). The RMS is a neurogenic pathway by which newly generated neurons migrate from the subventricular zone of the CNS towards the olfactory bulb; in rodents, this facilitates continuous replenishment of dying neurons of the olfactory system.

Ectopic lymphoid tissues

Newly-formed lymphoid tissues arising at non-determined sites within affected tissues due to unresolved inflammatory processes. Much like secondary lymphoid tissues such as lymph nodes, spleen and Peyer's patches, ectopic (also known as tertiary) lymphoid organs harbour B cell follicles and support the induction and/or maintenance of adaptive immune responses. The formation of ectopic lymphoid tissues has been implicated in the pathogenesis of a wide range of chronic inflammatory conditions, including several autoimmune diseases.

Pannus

Abnormal vessel-rich hypertrophic fibrovascular tissue developing from inflamed synovium within affected joints during rheumatoid arthritis. Owing to its infiltrative tumour-like growth, pannus formation leads to the progressive destruction of synovium, cartilage and bone during later stages of rheumatoid arthritis. The development of tertiary lymphoid tissue within the pannus has been described.

slanDCs

Human DCs that are characterized by specific expression of the 6-sulfo N-acetyllactosamine (slan) instead of cutaneous lymphocyte antigen (CLA) or P-selectin glycoprotein ligand 1. SlanDCs are capable of producing very high levels of pro-inflammatory mediators and are associated with chronic inflammatory and autoimmune diseases of the skin.

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Worbs, T., Hammerschmidt, S. & Förster, R. Dendritic cell migration in health and disease. Nat Rev Immunol 17, 30–48 (2017). https://doi.org/10.1038/nri.2016.116

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