Development of the immune system

Lymph nodes are highly organized organs and essential for regulation of the adaptive immune system. Although lymph nodes are highly organized, embryonic lymphoid node formation starts with the interaction of a subset of type 3 Innate Lymphoid Cells (ILC3), previously named Lymphoid Tissue Inducer (LTi) cells, with mesenchymal organizer cells at pre-determined locations throughout the body (Figure 1).

The ILC family has been recently described and is now recognized as essential for several immunological functions. Interestingly, these innate cells are essential for development of the adaptive immune system by their involvement in the embryonic formation of lymph nodes.


Previously, I have shown that retinoic acid is essential for the differentiation of both the ILC3 as the mesenchymal organizer cells and hence essential for embryonic lymph node formation. More importantly, altering levels of the raw material for retinoic acid, vitamin A, within the diet of the pregnant mouse affected the size of lymph nodes in her offspring at adult age. Therefore, the diet of the pregnant mother is important for the proper development of the immune system within the embryos and has a lifelong effect on the immunity of her offspring. Basically, you are what your mother ate.


 

404 Figure 1: Phases of embryonic lymph node formation. a) Retinoic acid, possibly produced by nerve fibers, induces the expression of CXC chemokine ligand 13 (Cxcl13) by mesenchymal cells. Cxcl13 then attracts lymphoid tissue inducer (LTi) precursor cells from the blood to form the first cell clusters. Clustering of pre-LTi cells facilitates signaling through TRANCER. b) This leads to the induction of lymphotoxin-α1ß2 (LTα1ß2) expression by pre-LTi cells, which differentiate into mature LTi cells. Interaction of LTα1ß2-expressing LTi cells with lymphotoxin-ß receptor (LTßR)-expressing stromal cells results in differentiation into stromal organizer cells, which are induced to express chemokines, adhesion molecules and cytokines. c) These factors support the attraction and retention of more hematopoietic cells, leading to lymph node growth. CCL, CC-chemokine ligand; E, embryonic day; ICAM1, intercellular adhesion molecule 1; IL-7, interleukin-7; MADCAM1, mucosal vascular addressin cell adhesion molecule 1;VCAM1, vascular cell adhesion molecule 1. From van de Pavert & Mebius, Nature Reviews Immunology 2010.

It is still unclear how lymph nodes are formed at specific locations, and possibly the nerve fibers and blood vessel bifurcations could play a role in establishing their location. Our aim is study the anatomical correlation of the structures in relation to lymph nodes and their associated lymphatic vasculature, and to study the role of nerve fibers in this process. This will be done by the use of light-sheet microscopy, which enables the whole mount acquisition of fluorescently stained mouse embryos up to E13.5 (Figure 2).

Also, my group will study other substances in the maternal diet that affect differentiation of key players involved in lymph node formation. These studies will provide insights into the ontogeny and functioning of the ILC3 family and provide knowledge on the requirements for the formation of embryonic lymph nodes.

The overall objective of my group is to characterize all players involved in development of the immune system, specifically in relation to the formation of lymph nodes and lymphatic vasculature.

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Figure 2: Whole-mount E13.5 mouse embryo fluorescently stained and imaged using  the Ultramicroscope (light sheet microscope, LaVision). (Serge van de Pavert)