CE15 - Immunologie, Infectiologie et Inflammation

Deciphering immune-licensing mechanisms of intestinal epithelial cells – IECLicensing

Submission summary

Inflammatory bowel diseases (IBDs) are debilitating diseases that affect profoundly the lifestyle of over 5 million persons worldwide. IBDs are characterized by alternating periods of remission, and relapse whose mechanisms are obscure. Imbalanced immune responses against commensal bacteria are the root of IBDs. To prevent inappropriate immune responses against the gut microbiota, several barriers are in place. In particular, intestinal epithelial cells (IECs) establish a pivotal link between commensal bacteria and the mucosal immune system. IECs are equipped with receptors that sense the tremendous quantity of microbes hosted in the gut. Thus, controlling IEC reactivity to commensal bacteria is a constant and delicate challenge, and the mechanisms involved in tuning such IEC responses remain elusive. Strikingly, we uncovered using a murine model of IBD that IEC acquired an immune-like pattern that depends on T lymphocytes. Therefore, our goal is to decipher the mechanisms and consequences of IEC inflammatory immune licensing. Based on robust data and meta-analysis we have conducted, we will dissect how a lymphocyte-derived cytokine endows IECs with immune-inflammatory behaviors. We will shed a light on new mechanisms of 1) Cytokine-driven dysbiosis 2) Mucosal T cell activation and polarization orchestrated by immune licensed IECs 3) Cellular, molecular and spatial heterogeneity of different subsets/states of Inflammatory IECs, and 4) Inflammatory experienced IECs that keep epigenetic marks of previous cytokine-driven activation with consequences on relapses. To extent physiological relevance for human IBDs, we will validate our discovery in humans. Our consortium employs innovative technologies (spatial transcriptomic analysis, third-generation sequencing, a patented system to culture organoids, CRISPR/Cas9 epigenome editing, microbiome analysis tools and relevant mice models) to achieve our goal in a timely manner.

Project coordinator

Monsieur Saïdi Soudja M'Homa (Centre régionnal de lutte contre le cancer - Centre Léon-Bérard)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

CRCL Centre régionnal de lutte contre le cancer - Centre Léon-Bérard
Ghent University - VIB Center for Inflammation Research
CRCL Centre régionnal de lutte contre le cancer - Centre Léon-Bérard

Help of the ANR 456,181 euros
Beginning and duration of the scientific project: September 2022 - 42 Months

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