Lymphoid cells, stromal cells and microbiota interact to define health and immunity of the host
Microbiota, lymphoid cells and stromal cells develop a crosstalk that allows maintaining homeostasis, organize defense, and resolve inflammation to restore tissue integrity. Deregulation of this crosstalk prolongs inflammation or prevents the healing process, resulting in chronic inflammatory and fibrotic pathologies. Our previous work has led us to define central actors among pro-inflammatory lymphoid and stromal cells, and to identify components of the symbiotic microbiota that efficiently modulate immunity.
Adaptive immunity comes into mainly 3 types of effector responses directed against intracellular microbes and tumors, large parasites or extracellular microbes. These responses are orchestrated by dendritic cells (DCs) and regulated by T (helper) Th1, Th2 and Th17 cells. Three types of ILCs have recently been described that mimic the activity of Th cells and that are termed ILC1, ILC2 and ILC3. As ILCs act promptly upon infection and injury, and express large amounts of effector cytokines, it is expected that they play an important role early in the regulation of immune responses. To directly explore this hypothesis, we have generated a panel of transgenic mice that allow for the timed ablation of each individual subset of ILCs, without damage to other immune cells. As ILCs are also involved in inflammatory pathology in response to chronic injury and metabolic stress, we explore how ILCs can be manipulated to restore normal immune functions, and extend our findings to human disease.
The development, homeostasis and pathology of the host are influenced at many levels by the symbiotic microbiota. In particular, we have shown how microbiota regulates the activity of RORgt+ ILCs and T cells. Large projects around the world aim at dissecting the impact of microbiota on human health. We focus on the study of specific bacterial compounds shown to affect the activity of ILCs, such as peptidoglycans recognized by the Nod1 and Nod2 innate receptors, and polysaccharides recognized by TLRs and MHC molecules. We explore the effect of these metabolites on the regulation of immune responses, as well as on the host nervous system that modulates immunity. We also explore the regulation of the microbiota composition and activity by RORgt+ pro-inflammatory cells and the different subsets of ILCs during homeostasis and inflammation. These studies are performed in collaboration with clinical and industrial partners interested in the development of health-efficient probiotics.
The STROMA group, headed by Lucie Peduto, is exploring the fundamental role of stromal cells in the organization of inflammation and tissue repair, more specifically in the context of infection, fibrosis and cancer. The generation of proinflammatory stromal cells by perivascular progenitors is controlled in models that allow for transient ablation of these cells and their progeny in vivo, to assess their impact on immune responses and disease pathogenesis. We further perform a comprehensive analysis of stromal cells in the intestine and injured tissues to characterize distinct functional subsets of stromal cells and their progenitors among perivascular cells. Using new reporter mice for such stromal subsets, as well as the ILC-ablation systems mentioned above, we aim at developing an integrated understanding of the crosstalk between stromal and lymphoid cells during homeostasis and disease. Please see our group website for more information on our team and projects (http://www.pasteur.fr/research/stromalcells).
Symbiotic bacteria (red) in close contact with the intestinal epithelium (green and blue). Many types of cells are involved in the interaction of the host with its symbiotic microbiota to maintain a functional and healthy interaction. Such cells include lymphoid cells and stromal cells.