Description du projet
L’interaction des cellules immunitaires avec la niche des cellules souches épithéliales dans le pancréas
Les lymphocytes T régulateurs (Treg) sont capables de moduler les cellules souches épithéliales, essentielles à l’homéostasie et à la régénération tissulaires. De récentes preuves indiquent que les cellules lymphoïdes innées de type 2 (ILC2) contribuent à l’expansion des Treg et pourraient ainsi influencer la niche des cellules souches. De précédents travaux réalisés dans le cadre du projet PanILC, financé par l’UE, ont montré que l’activation des ILC2 dans le pancréas augmentait le nombre de Treg, suggérant une potentielle interaction entre les deux populations cellulaires. Lors du projet PanILC, les scientifiques se focaliseront sur le rôle et sur la diaphonie des ILC2 et des Treg dans la pancréatite. Dans la mesure où la pancréatite constitue un facteur de risque important pour le développement du cancer du pancréas, les résultats du projet permettront de dévoiler des connaissances primordiales sur le rôle de ces types de cellules dans le développement tumoral.
Objectif
Regulation of the epithelial stem cell compartment is critical for tissue homeostasis and regeneration. Consequently, imbalance in this process, through acquisition of somatic mutations for instance, may give rise to tumorigenesis. Emerging reports reveal that regulatory T cells (Tregs) can modulate epithelial stem cell dynamics in the skin, while type 2 innate lymphoid cells (ILC2s) are known to influence tissue-regeneration. Recent work in our laboratory has elucidated that ILC2s crosstalk is essential for local Tregs expansion. We hypothesize that tissue-resident ILC2s influence the stem cell niche by recruiting and regulating Tregs, and that such a mechanism could be key to tissue regeneration as well as tumor development.
Preliminary data in the lab suggest that the intraperitoneal injection of the potent ILC2 inducer IL-33 in mice activates ILC2 in the pancreas, and that a concomitant increase in Treg numbers is observed in this organ. This raises the possibility of the existence of a crosstalk between ILC2s and Tregs in the pancreas upon inflammation, such as in the case of pancreatitis. Given the considerable attention brought lately on the ability of Tregs to develop tissue-promoting capacities, we postulate that regeneration of the exocrine pancreas following pancreatitis may be driven by such pancreatic Tregs upon their “priming” by ILC2.
The present project will therefore focus on understanding the role of ILC2 and Tregs and their possible crosstalk in pancreatitis development, as well as in the regeneration process that follows, i.e. the interaction of these immune cells with epithelial progenitors. As pancreatitis is a major risk factor for the development of pancreatic cancer, the resulting observations will then be extended to the analysis of the role of ILC2/Treg crosstalk in tumor development in an orthotopic mouse model of pancreatic tumours as well as in a genetic mouse model of pancreatic adenocarcinoma.
Champ scientifique
- medical and health sciencesclinical medicineoncologyprostate cancer
- medical and health sciencesbasic medicineimmunology
- medical and health sciencesmedical biotechnologycells technologiesstem cells
- medical and health sciencesclinical medicineoncologypancreatic cancer
- medical and health sciencesbasic medicinephysiologyhomeostasis
Programme(s)
Régime de financement
MSCA-IF-EF-ST - Standard EFCoordinateur
CB2 1TN Cambridge
Royaume-Uni