Keystones in lymph node development

Abstract

New molecular markers are constantly increasing our knowledge of developmental processes. In this review article we have attempted to summarize the keystones of lymphoid tissue development in embryonic and pathological conditions. During embryonic lymph node development in the mouse, cells from the anterior cardinal vein start to bud and sprout, forming a lymph sac at defined sites. The protrusion of mesenchymal tissue into the lymph sacs forms the environment, where so-called 'lymphoid tissue inducer cells' and 'mesenchymal organizer cells' meet and interact. Defects of molecules involved in the recruitment and signalling cascades of these cells lead to primary immunodeficiency diseases. A comparison of molecules involved in the development of secondary lymphoid organs and tertiary lymphoid organs, e.g. in autoimmune diseases, shows that the same molecules are involved in both processes. This has led to the hypothesis that the development of tertiary lymphoid organs is a recapitulation of embryonic lymphoid tissue development at ectopic sites.

Fig. 1

Development of the lymph sacs in the mouse, through budding and sprouting of endothelial cells. The autonomous endothelial cells of the anterior cardinal vein start to express LYVE1 around E9.0–9.5. The cells on one side of the vein follow the lymphatic bias and start to express Prox1. For the budding and sprouting of lymphendothelial cells at E10.5–11.5, the Prox1 expression of the lymphendothelial cell precursors cells is a prerequisite to react to a guiding signal. VEGF-C seems to be involved in this guidance and signalling process. When the lymphendothelial cells start to migrate, they already express most molecules specific for the lymphendothelium such as LYVE1, Prox1, CCL21 and VEGFR-3. Around E11.5–12.5 the lymphatic and the blood vascular system are separated and the lymphatic vessel development and the lymph node development follow different pathways emerging from the lymph sacs. (Modified after Oliver & Alitalo, 2005.)

Fig. 2

Development from the multipotent stem cell to the lymphoid tissue inducer cell in the mouse. The IL-7Rα⁺ c-Kit^low Sca1^low-expressing cells can be found in the fetal liver around E12.5–14.5. The absence of these cells in Ikaros^−/– mice shows the importance of this molecule in the generation of these cells. The multipotent character of these LTi progenitor cells is demonstrated by their ability to develop into lymphoid tissue inducer cells as well as T, B, NK and dendritic cells. For differentiation towards the CD3⁻CD4⁻CD45⁺IL-7Rα⁺-expressing LTi cells the molecules Id2 and RORγt are required. After differentiation into LTi cells, those cells can be detected at different peripheral sites, e.g. the spleen and the lymph node anlagen. For the recruitment of the inducer cells to the LN anlagen a possible role for TRANCE as a guiding signal is still under discussion.

Fig. 3

Activation of NF-κB via the classical and the alternative pathway. Signalling via the LTβR can initiate both NF-κB activation pathways. The classical pathway leads to the expression of the inflammatory molecules VCAM1, MIP-1β and MIP-2, and an increase of p100. The first step in this cascade is the activation of the β unit of the IKK complex. This activated IKKβ complex leads to phosphorylation and ubiquitination of the IκBα, which allows the p50-RelA heterodimer to translocate to the nucleus and bind to the DNA. The alternative pathway follows a similar mechanism: after activation of the IKKα complex, p100 is phosphorylated and processed to p52. The remaining p52-RelB heterodimer induces the expression of the homeostatic cytokines CCL19, CCL21, CXCL13 and CXCL12, after translocation into the nucleus. (Modified from Weih & Caamano, 2003.)

Fig. 4

Schematic view of a lymph node (LN). The composition of the LN can be divided into different regions. For didactic reasons the distinct functions are displayed in different sections. The cortex consists mainly of B cells organized as primary or secondary follicles. The migration of these cells towards the follicles is mediated by follicular dendritic cells (FDC) also located in the cortical region. T cells migrate to the paracortical region, neighbouring the cortex. They interact with the interdigitating dendritic cells (IDC), also present in the paracortical region. The central region, the medulla, mostly contains plasma cells and B cells. The lymphocytes enter the LN via the afferent lymphatic vessel or through transmigration of the high endothelial venules (HEV). Both systems, the lymph vasculature and the blood vasculature, are connected via a conduit system, and both drain into the efferent lymph vessel via the medullary sinus. (Modified from Pabst, 2004.)