Projektbeschreibung
Wie Immunzellen mit der epithelialen Stammzellnische in der Bauchspeicheldrüse interagieren
Regulatorische T-Zellen (Treg) sind in der Lage, epitheliale Stammzellen zu modulieren, die überaus wichtig für Gewebehomöostase und -regeneration sind. Neue Erkenntnisse deuten nun darauf hin, dass lymphoide Typ 2-Zellen des angeborenen Immunsystems (ILC2) die Treg-Expansion unterstützen und somit die Stammzellnische beeinflussen können. Frühere Arbeiten des EU-finanzierten Projekts PanILC hatten ergeben, dass die Aktivierung von ILC2 in der Bauchspeicheldrüse die Treg-Anzahl erhöht, was auf eine mögliche Interaktion zwischen den beiden Zellpopulationen hindeutet. Im Rahmen von PanILC wird sich das Wissenschaftsteam auf die Rolle der lymphoiden Typ 2-Zellen des angeborenen Immunsystems und der regulatorischen T-Zellen sowie das Wechselspiel zwischen ihnen bei Pankreatitis konzentrieren. Da Pankreatitis ein wichtiger Risikofaktor für die Entstehung von Bauchspeicheldrüsenkrebs ist, werden die Projektergebnisse wichtiges Wissen über die Funktion dieser Zelltypen bei der Tumorentwicklung offenbaren.
Ziel
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.
Wissenschaftliches Gebiet
- 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
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