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Dendritic cell subsets in T cell programming: location dictates function

Abstract

Dendritic cells (DCs) can be viewed as translators between innate and adaptive immunity. They integrate signals derived from tissue infection or damage and present processed antigen from these sites to naive T cells in secondary lymphoid organs while also providing multiple soluble and surface-bound signals that help to guide T cell differentiation. DC-mediated tailoring of the appropriate T cell programme ensures a proper cascade of immune responses that adequately targets the insult. Recent advances in our understanding of the different types of DC subsets along with the cellular organization and orchestration of DC and lymphocyte positioning in secondary lymphoid organs over time has led to a clearer understanding of how the nature of the T cell response is shaped. This Review discusses how geographical organization and ordered sequences of cellular interactions in lymph nodes and the spleen regulate immunity.

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Fig. 1: Functionally specialized conventional and non-conventional dendritic cell subsets and related lineages.
Fig. 2: Immunologic microanatomy of an LN.
Fig. 3: Immunologic microanatomy of the spleen.

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Acknowledgements

The author thanks all the members of her lab, A. Williams, S. Cassel and many wonderful colleagues at Yale for helpful discussion over the years and critical review of this manuscript. This work was supported by R01 AI108829, CTSA UL1 TR001863 and P01HL13281901.

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Nature Reviews Immunology thanks J. Cyster, S. Mueller and the other, anonymous reviewer(s) for their contribution to the peer review of this work.

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Glossary

Secondary lymphoid organs

(SLOs). Structures that are organized to facilitate antigen concentration, resulting in T and B cell activation or tolerance. In contrast to the primary lymphoid structures, thymus and bone marrow, SLOs include lymph nodes, spleen and mucosa-associated lymphoid tissues.

Cross-presentation

Processing of extracellular antigens for MHC class I (MHCI) for presentation to CD8+ T cells; this is primarily accomplished by type 1 conventional dendritic cells.

DC activation

A process that is alternatively called dendritic cell (DC) maturation, which can cause confusion with the developmental maturation programme that also occurs in tissues after immigration from the bone marrow as pre-specified DC subset precursors. Therefore, in this Review, the term DC activation is used to summarize the variety of changes the DC undergoes after innate stimuli are detected that induce T cell stimulatory signals, antigen processing and presentation and changes in chemokine receptor expression.

High endothelial venules

(HEVs). Unique post-capillary venules in secondary lymphoid organs, except the spleen, where lymphocytes exit the bloodstream into the lymph node paracortex.

Antigen dose

This can be thought of as the weighted average of the ratio of antigen-bearing dendritic cells (DCs) to cognate T cells, the amount of cognate peptide–MHC per DC, the duration of DC–T cell interaction and the affinity of the T cell receptor for that antigen.

Chemokines

Small basic chemotactic proteins that guide migration of motile cells by binding to G protein-coupled receptors.

Sphingosine-1-phosphate

(S1P). A lipid that acts as a chemoattractant and is most concentrated in blood and lymph; multiple S1P receptors direct dendritic cell and lymphocyte migration.

Interfollicular zone

(IFZ). The area of the lymph node immediately beneath the subcapsular sinus (SCS) (approximately 0–30 µm from the SCS) and in between B cell follicles. The medial section of the IFZ overlaps with the outer paracortex and is part of the T cell–B cell border.

Paracortex

The region of the lymph node medial to the B cell follicles in the cortex but distal to the medulla and efferent lymphatics. This is the area where T cells are typically distributed and therefore is often referred to as the T cell zone. High endothelial venules are also present in this region. The paracortex can be divided into an inner (90 µm from the subcapsular sinus (SCS)) and outer (30 µm from the SCS) region.

Follicular dendritic cells

(FDCs). Non-haematopoietic cells in the follicle of secondary lymphoid organs that capture and present antigen and immune complexes to B cells.

Fibroblastic reticular cells

(FRCs). Non-haematopoietic stromal cells in the T cell zone of secondary lymphoid organs that produce chemokines and express surface molecules necessary for lymphocyte and dendritic cell migration.

Epstein–Barr virus induced gene 2

(EBI2). A receptor that responds to the oxysterol ligands 7α,25-hydroxycholesterol and 7α,27-hydroxycholesterol and regulates B cell, T cell and dendritic cell (DC) positioning within secondary lymphoid organs. Signalling through EBI2 is particularly important for localizing lymphocytes and type 2 conventional DCs to the T cell–B cell border.

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Eisenbarth, S.C. Dendritic cell subsets in T cell programming: location dictates function. Nat Rev Immunol 19, 89–103 (2019). https://doi.org/10.1038/s41577-018-0088-1

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