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Organogenesis of lymphoid tissues

Nature Reviews Immunology volume 3, pages 292–303 (2003)Cite this article

An Erratum to this article was published on 01 June 2003

Key Points

  • For the formation of lymph nodes and Peyer's patches, lymphotoxin (LT)α1β2-mediated signalling through the lymphotoxin-β receptor (LTβR) is essential. LTα1β2 is expressed by haematopoietic cells, whereas LTβR is present on stromal cells.

  • The cells that express LTα1β2 are CD3−CD4+CD45+ cells. In the absence of these cells, lymph nodes and Peyer's patches can not form.

  • The cells that express LTβR are further characterized by expression of vascular-cell adhesion molecule 1 (VCAM1) and intercellular adhesion molecule 1 (ICAM1). These cells produce the chemokines CXCL13 and CCL19.

  • Binding of CD3−CD4+CD45+ cells to stromal cells requires activation of the β1 integrin on CD3−CD4+CD45+ cells. This allows active α4β1 integrin binding to VCAM1 on stromal cells, after which LTα1β2-mediated signalling through LTβR can take place.

  • After LTβR signalling, two NF-κB pathways are activated. Activation of the classical NF-κB pathway is required for the induction of VCAM1, whereas activation of the alternative pathway, which requires NF-κB-inducing kinase (NIK), is necessary for the induction of chemokines (that is, CXCL13).

  • The chemokine CXCL13 is essential for lymphoid organogenesis. Its role in this process could be manifold, as it might induce activation of β1 integrin, attract CD3−CD4+CD45+ cells and be involved in the induction of LTα1β2 expression.

  • Cell clustering of haematopoietic cells and stromal cells is essential for lymphoid organogenesis. It allows cellular signalling required for further development of the structure.

  • Throughout the process of lymphoid organogenesis, LTα1β2 is important, because it is required for the formation, as well as the organization, of the lymphoid organs. LTα1β2 could have a similar role in establishing organized tertiary lymphoid structures during inflammatory reactions.

Abstract

The development of lymphoid organs depends on the correct expression of several molecules within a defined timeframe during ontogeny. Although this is an extremely complex process, with each secondary lymphoid tissue requiring subtly different signals, a common framework for lymphoid development is beginning to emerge. Drawing on studies of lymph nodes, Peyer's patches and nasal-associated lymphoid tissue, an integrative model of lymphoid-tissue development, involving adhesion molecules, cytokines and chemokines, which emphasizes the role of interactions between CD3−CD4+CD45+ 'inducer' cells and VCAM1+ICAM1+ stromal 'organizer' cells is presented.

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Figure 1: Development of lymphatic endothelium on the basis of Prox1 expression.
Figure 2: Time line of development of the various lymphoid organs.
Figure 3: The generation of CD3−CD4+CD45+ cells.
Figure 4: Model for the generation of LTα1β2-expressing CD3−CD4+CD45+ cells.
Figure 5: Model of increasing dependency on LTα1β2 for the initial cell clustering.
Figure 6: Model for lymphoid-organ development.
Figure 7: Organization of lymphoid organs is mediated by lymphoid chemokines.

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Acknowledgements

I thank T. Cupedo, T. O'Toole and G. Kraal for critically reading the manuscript and for their useful suggestions. The work in my laboratory is supported by grants from the Netherlands Organisation for Scientific Research.

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  1. Department of Molecular Cell Biology, VU University Medical Center, v.d. Boechorststraat 7, Amsterdam, 1081 BT, The Netherlands

    Reina E. Mebius

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DATABASES

LocusLink

CCL19

CCL21

CR1

CXCL12

CXCL13

γc

ICAM1

Id2

Ikaros

IL-7Rα

Jak3

LIGHT

LTα1β2

LTβR

NIK

Prox1

RORγ

TNF

TNFR p55

TRAF6

TRANCE

VCAM1

OMIM

Hashimoto thyroiditis

rheumatoid arthritis

Sjögren syndrome

Glossary

LYMPHOTOXIN

(LT). This protein belongs to the tumour-necrosis factor family and can be produced as a secreted homotrimer, LTα3, or as a membrane-bound heterotrimer, LTα1β2. The heterotrimer LTα1β2 binds to the lymphotoxin-β receptor (LTβR).

ALYMPHOPLASIA

(aly). A spontaneous mutation characterized by the systemic absence of lymph nodes and Peyer's patches. The gene responsible for this phenotype was shown to encode nuclear factor-κB-inducing kinase (NIK).

IKAROS

This gene encodes a family of zinc-finger transcription factors that regulate transcription required for the development of all lymphoid lineages, as well as lymph nodes and Peyer's patches.

ID2

A helix-loop-helix protein that can inhibit transcription factors with a basic helix-loop-helix motif. Besides its role in lymphoid organogenesis, Id2 is required for the generation of natural killer cells.

RETINOID-RELATED ORPHAN RECEPTOR γ

(RORγ). An orphan nuclear hormone receptor that regulates the survival of CD4+CD8+ thymocytes and is essential for the development of lymph nodes and Peyer's patches.

LYMPHOID CHEMOKINES

These are constitutively expressed in lymphoid tissues and mediate the formation and maintenance of micro-domains in lymphoid organs.

HIGH ENDOTHELIAL VENULES

(HEVs). Specialized venules found in lymphoid tissues, which are the site of entry for lymphocytes from the bloodstream into lymph nodes and Peyer's patches.

PAUCITY OF LYMPH NODE T CELLS

(plt). A mutation that leads to the loss of expression of the chemokines CCL19 and CCL21 in lymphoid organs, resulting in disturbed migration of CCR7-expressing T cells and mature dendritic cells.

FOLLICULAR DENDRITIC CELLS

(FDCs). These stromal cells present immune complexes to B cells in the B-cell follicles.

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Mebius, R. Organogenesis of lymphoid tissues. Nat Rev Immunol 3, 292–303 (2003). https://doi.org/10.1038/nri1054

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