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New insights into the development of lymphoid tissues

Nature Reviews Immunology volume 10, pages 664–674 (2010)Cite this article

Subjects

Key Points

  • The earliest event in lymph node development is the initial clustering of lymphoid-tissue inducer (LTi) cells at the location where lymph nodes will form. Attraction to this location is regulated by expression of CXC-chemokine ligand 13 (CXCL13). Recent studies suggest that this might be induced by retinoic acid produced by nearby nerve fibres.

  • Both lymph node and Peyer's patch development require the induction of lymphotoxin-α1β2 (LTα1β2) expression by LTi cells, which enables them to interact with lymphotoxin-β receptor (LTβR) expressed by stromal organizer cells. Signalling through LTβR on stromal organizer cells leads to the expression of chemokines, adhesion molecules and cytokines that are required for the attraction, retention and survival of haematopoietic cells in the developing lymphoid tissue.

  • The formation of mucosal-associated lymphoid tissues differs from the formation of lymph nodes and Peyer's patches. For nasopharynx-associated lymphoid tissues, the homeostatic chemokines are not needed, whereas for tear duct-associated lymphoid tissue LTi cells are not necessary, and both can form independently of LTβR signalling.

  • During chronic inflammation tertiary lymphoid structures form directly at the site of inflammation. When they develop in response to a viral infection they contribute to the production of antiviral immunity and can be viewed as beneficial for the host. By contrast, those that develop in autoimmune diseases may support the activation of autoreactive cells.

Abstract

Secondary lymphoid organs are important locations for the initiation of adaptive immune responses. They develop before birth, and their formation requires interaction between lymphotoxin-α1β2-expressing lymphoid-tissue inducer cells and lymphotoxin-β receptor-expressing stromal organizer cells. Here, we discuss new insights into the earliest phases of peripheral lymph node and Peyer's patch formation that occur before lymphotoxin-β receptor signalling and suggest a role for the developing nervous system. In addition, we discuss the differing requirements for the postnatal formation of mucosa-associated lymphoid tissues and tertiary lymphoid structures that develop at sites of chronic inflammation.

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Figure 1: Differentiation of lymphoid-tissue inducer cells from interleukin-7 receptor-α+ lymphoid progenitors.
Figure 2: Phases of lymph node formation.
Figure 3: Phases of Peyer's patch formation.

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Acknowledgements

We thank A. Baptista, G. Kraal, R. Roozendaal and T. O'Toole for critically reading the manuscript. The authors are supported by a Netherlands Genomics Institute (NGI)-Horizon breakthrough project (NGI 40-41009-98-9077) to S.A.v.d.P. and a Netherlands Organization for Scientific Research-Earth and Life Sciences (NWO-ALW) Top grant (09.048) to R.E.M.

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  1. Department of Molecular Cell Biology and Immunology, VU University Medical Center, P.O. BOX 7057, Amsterdam, 1007, MB, The Netherlands

    Serge A. van de Pavert & Reina E. Mebius

  2. Serge A. van de Pavert & Reina E. Mebius

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Glossary

Peyer's patches

Secondary lymphoid organs present in the small intestine (mostly in the ileum). They occur on the intestinal wall, opposite the line of attachment of the mesentery, the antimesenteric border. Peyer's patches consist of a dome area, B cell follicles and interfollicular T cell areas. High endothelial venules are present mainly in the interfollicular areas.

Autoimmune regulator

(AIRE). A transcription factor expressed mainly in the thymus by medullary thymic epithelial cells, but also by stromal cells in secondary lymphoid organs. It is involved in the transcription of diverse tissue-restricted antigens that, once processed and presented, promote the negative selection of self-reactive T cells.

Central tolerance

The lack of self responsiveness that occurs during lymphocyte development in the central lymphoid organs. B cell progenitors in the bone marrow and T cell progenitors in the thymus that strongly recognize self antigen either undergo further rearrangement of antigen receptor genes to avoid reactivity to self or are deleted by apoptosis.

Lymphotoxin-α1β2

(LTα1β2). A member of the tumour necrosis factor family that can be produced as a secreted homotrimer, LTα3, or as a membrane-bound heterotrimer, LTα1β2, which binds to lymphotoxin-β receptor (LTβR). Lymphoid-tissue inducer cells express LTα1β2,and signalling through LTβR expressed by stromal organizer cells induces the expression of molecules required for lymph node and Peyer's patch formation.

E2A-encoded proteins

The E2A gene locus encodes two basic helix–loop–helix transcription factors, E12 and E47, which are essential for B cell development. For induction of gene transcription, these E proteins bind an E box motif in the DNA.

Follicular dendritic cells

Specialized non-haematopoietic stromal cells that reside in the lymphoid follicles and germinal centres. These cells have long dendrites, but are not related to dendritic cells, and carry intact antigen on their surface. They are crucial for the optimal selection of B cells that produce high-affinity antibody.

Fibroblastic reticular cells

Stromal cells present in T cell areas of secondary lymphoid organs. These stromal cells surround the fine tubular network of collagen fibres (known as conduits) through which small molecules can rapidly reach the centre of lymphoid organs. In addition, fibroblastic reticular cells are in close contact with haematopoietic cells in secondary lymphoid organs.

RET

A transmembrane tyrosine kinase receptor that has several co-receptors and ligands. It is required for the migration of neural crest cells in the gut wall, as well as for their subsequent differentiation and aggregation into ganglia. In addition, RET is essential for the aggregation of haematopoietic cells during Peyer's patch formation.

Cryptopatches

Clusters of cells that are located at the base of the villi in the intestine. The cells are characterized by a LIN−KIT+CD90− phenotype and by the expression of RORγt and other molecules that are typical of fetal lymphoid-tissue inducer cells. Cryptopatches do not develop in RORγt-deficient mice.

Omentum

A generic term that refers to folds of the peritoneum. The lesser omentum consists of two layers of peritoneum and passes between the liver and the stomach. The greater omentum consists of four layers of peritoneum that extend below the stomach.

B-1 B cells

A group of self-renewing, autoreactive B cells with a limited B cell receptor repertoire. These cells are mainly found in the peritoneal cavity and the pleural cavity.

Peripheral tissue-restricted antigens

(Also known as tissue-specific antigens). Proteins that are restricted in their expression to specific tissues in the periphery. To induce and maintain T cell tolerance to these proteins, they are expressed by non-haematopoietic cells in the thymus and secondary lymphoid organs.

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van de Pavert, S., Mebius, R. New insights into the development of lymphoid tissues. Nat Rev Immunol 10, 664–674 (2010). https://doi.org/10.1038/nri2832

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