Descrizione del progetto
Interazione delle cellule immunitarie con la nicchia delle cellule staminali epiteliali nel pancreas
Le cellule T regolatorie (Treg) sono in grado di modulare le cellule staminali epiteliali che sono centrali per l’omeostasi e la rigenerazione dei tessuti. Vi sono sempre più prove che indicano come le cellule linfoidi innate di tipo 2 (ILC2) contribuiscano all’espansione delle Treg e possano quindi influenzare la nicchia delle cellule staminali. Il lavoro precedente del progetto PanILC, finanziato dall’UE, ha rivelato che l’attivazione di ILC2 nel pancreas aumenta il numero di Treg, suggerendo una potenziale interazione tra le due popolazioni di cellule. Nel corso di PanILC, gli scienziati si concentreranno sul ruolo e sull’interazione tra ILC2 e Treg nella pancreatite. Poiché la pancreatite è uno dei principali fattori di rischio per lo sviluppo del cancro al pancreas, i risultati del progetto sveleranno importanti conoscenze sul ruolo di questi tipi di cellule nello sviluppo del tumore.
Obiettivo
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.
Campo scientifico
- 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
Programma(i)
Argomento(i)
Meccanismo di finanziamento
MSCA-IF-EF-ST - Standard EFCoordinatore
CB2 1TN Cambridge
Regno Unito