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Glaubitz, Juliane; Wilden, Anika; Golchert, Janine; Homuth, Georg; Voelker, Uwe; Broeker, Barbara M.; Thiele, Thomas; Lerch, Markus M.; Mayerle, Julia; Aghdassi, Ali A.; Weiss, Frank U. and Sendler, Matthias (2022): In mouse chronic pancreatitis CD25(+)FOXP3(+) regulatory T cells control pancreatic fibrosis by suppression of the type 2 immune response. In: Nature Communications, Vol. 13, No. 1, 4502

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The function of T regulatory cells in the tissue fibrosis in chronic pancreatitis is not fully understood. Here the authors use a mouse model of chronic pancreatitis to show that Treg cells reduce IL-4 mediated chronic inflammation in the pancreas associated with M2-like macrophages in vivo. Chronic pancreatitis (CP) is characterized by chronic inflammation and the progressive fibrotic replacement of exocrine and endocrine pancreatic tissue. We identify Treg cells 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 results 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(+) Treg cells 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 Treg cells as key regulators of the type-2 immune response and of organ remodeling during CP. The Treg/Th2 axis could be a therapeutic target to prevent fibrosis and preserve functional pancreatic tissue.

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