Ontogeny programs the development of lymphocytes and their recruitment to secondary lymphoid tissues. These tissues collect antigens and mount adaptive immune responses to potential pathogens. The recruitment, activation and migration of lymphocytes require a highly organized network of stromal and hematopoietic cells that orchestrate each step in the development of an immune response. Furthermore, an immune response induces the development of the immune system itself by promoting the generation of new lymphoid tissues and the differentiation of lymphocytes. In that context, microbes, and more generally injured cells and tissues, are not only triggers and targets of destructive immunity, but also the architects of a mature immune system. The best example of such a constructive partnership between microbes and the immune system is found in the intestine, where billions of bacteria have established a mutualistic relationship with the host not only for optimal digestion, but also for robust defense against pathogens and injury. We decipher how symbiotic bacteria induce ‘physiologic infammation’ and the consequent maturation of the immune system for the maintenance of intestinal homeostasis. In particular, we dissect the role of innate lymphoid cells and active stromal cells in health and disease of the intestine, and beyond.

1. Symbiotic microbiota and the development of the immune system

The last few years have witnessed a vast expansion of data showing the impact of the symbiotic microbiota on the development of the immune system, on intestinal homeostasis and on the inflammatory state of the host. Our own data demonstrate that symbiotic bacteria induce the formation of isolated lymphoid tissues in the intestine, and control the recruitment and differentiation of pro-inflammatory lymphocytes, such as Th17 cells and IL-22-producing NKp46⁺ cells. We aim at deciphering the complex dialogue between symbiotic microbes and the immune system, during homeostasis and disease.

2. Intestinal lymphoid cells

We show that a particular set of immune cells, the RORγt⁺ innate lymphoid cells (ILCs), are programmed to develop and function ahead of the bacterial colonization of the gut. These cells are the prime producers of IL-17 and IL-22, both critical cytokines to boost the defense capacity of the intestinal epithelium and to recruit phagocytes that eliminate penetrating bacteria. Upon colonization with symbiotic bacteria, this program is repressed; upon damage and infection, it is amplified to force a return of the intestine to homeostasis. When these cells are absent altogether, the intestine tips over to fatal intestinal immunopathology caused by bacterial penetration.

3. Stromal cells in immunity

Stromal cells, including epithelial, endothelial and mesenchymal cells, play a central organizing role in the guidance and survival of leukocytes in lymphoid or inflamed tissues. In the intestine for example, epithelial cells translate and transfer information on the symbiotic microbiota from the lumen to the internal stromal cells and leukocytes, and orchestrate early activation steps of the immune system. Lymphoid stromal (LS) cells express structural chemokines, adhesion molecules and cytokines that are required to stabilize lymphoid tissues, and are generated early during the fetal development of lymphoid tissues, and are re-induced during inflammation. During chronic inflammation, such LS cells organize the formation of tertiary lymphoid tissues that aggravate disease. We aim at identifying stromal cells subsets that play fundamental role in immunity.

Keywords: Lymphoid tissues, lymphoid stromal cells, intestinal homeostasis, Th17 cells, pro-inflammatory immunity

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