In chronic pancreatitis CD25+/Foxp3+ regulatory T-cells control pancreatic fibrosis by suppression of the type 2 immune response

Abstract Chronic pancreatitis (CP) is characterized by chronic inflammation and the progressive fibrotic replacement of exocrine and endocrine pancreatic tissue. We identified Tregs as central regulators of the fibroinflammatory reaction by a selective depletion of Foxp3-positive cells in a transgenic mouse model (DEREG-mice) of experimental CP. In Treg-depleted DEREG-mice, the induction of CP resulted in a significantly increased stroma deposition, the development of exocrine insufficiency and significant weight loss starting from day 14 after disease onset. In CP, Foxp3+/CD25+ Tregs suppress the type-2 immune response by a repression of Gata3+ T-helper cells (Th2), Gata3+ innate lymphoid cells type 2 (ILC2) and CD206+ M2-macrophages. A suspected pathomechanism behind the fibrotic tissue replacement may involve an observed dysbalance of Activin A expression in macrophages and of its counter regulator Follistatin. Our study identified Tregs as key regulators of the type-2 immune response and of organ remodeling during CP. The Treg-triggered immune response could be a therapeutic target to prevent fibrosis and preserve functional pancreatic tissue.