ILCHI

Innate lymphoid cells in intestinal homeostasis and immunity

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 Obiettivo del progetto (Objective)

'The nuclear hormone receptor RORγt marks a family of pro-inflammatory lymphoid cells, which includes adaptive IL-17-producing helper T cells (Th17), as well as subsets of innate lymphoid cells (ILCs), such as lymphoid tissue inducer (LTi) cells and IL 22-producing NKp46 cells. These cells are required for the development of lymphoid tissues, homeostasis with symbiotic microbiota and defense against pathogens. The development and activity of RORγt ILCs are programmed to pre-empt intestinal colonization by bacterial symbionts and in turn, symbionts regulate the activity of RORγt ILCs. Thus, an equilibrated crosstalk between RORγt ILCs, microbiota, pathogens and adaptive immunity develops that is critical for intestinal homeostasis, a loss of which leads to inflammatory immunopathology. This project aims at understanding which and how symbiotic microbes induce and regulate RORγt ILCs, and how these cells control microbiota during homeostasis. To that end, GF mice will be colonized with symbiotic bacteria shown to correlate with RORγt ILC number and activity in normal mice. The mechanisms of regulation will then be dissected in vivo in a panel of mutant or antibody treated mice as well as in in vitro experiments. This study also aims at understanding how the homeostatic crosstalk between symbionts and RORγt ILCs breaks down during inflammatory pathology. In mice that lack RORγt ILCs, the structure of the bacterial community and propensity to develop immunopathology will be determined. Conversely, it will be tested whether inflammatory immunopathology leads to a disequilibrium between microbiota and ILCs. A better understanding of the mechanisms leading to a loss of homeostasis and immunopathological reactions is necessary to the design of new and more effective preventive and therapeutic strategies against intestinal immunopathologies. The study will be carried out in the Lymphoid Tissue Development Unit at Institut Pasteur in Paris.'

Introduzione (Teaser)

Understanding how inflammation is regulated and how aberrant control leads to pathophysiological conditions is the answer for providing efficient treatment.

Descrizione progetto (Article)

Inflammatory bowel diseases like Crohn's disease and ulcerative colitis manifest with chronic inflammation in the gastrointestinal tract. Current treatment mainly entails the administration of immunosuppressive drugs, inhibition of the tumour necrosis factor and, in extreme cases, surgical removal of the affected part of the intestine.

The team behind the EU-funded 'Innate lymphoid cells in intestinal homeostasis and immunity' (ILCHI) project wished to delineate how inflammation leads to such pathological conditions. Their work focused on the role of nuclear hormone receptor ROR?t, a surface antigen present on pro-inflammatory cells.

These ROR?t-expressing innate lymphoid cells (ILC3s) are required for the development of lymphoid tissues, for the interaction with symbiotic microbiota, and are implicated in the defence against pathogens.

There is a reciprocal regulation between symbiotic bacteria and ILC3s, leading to a fine equilibrium between the host and the symbionts. The scope of the ILCHI study was to delineate the mechanism underlying this crosstalk. To this end, scientists screened mice with deletions in one of the innate immune pathways and also looked at the impact of various cytokines.

Different immune cells imposed a different function on ILC3s, illustrating the complexity of ILC3 regulation. For this purpose, researchers generated a new transgenic mouse harbouring a specific and timely deletion of ILC3s. This is expected to provide key data on the role of ILC3s in immune system development, on the symbiotic microbiota and on inflammatory pathologies.

The generated information will support the development of novel treatment modalities based on re-establishing intestinal homeostasis rather than blocking pro-inflammatory immunity. In view of the recent association between the loss of intestinal homeostasis and the onset of autoimmunity in distant organs, ILCHI findings could be extrapolated for other autoimmune disturbances.