Regulatory T cell stability determines the efficiency of bile duct regeneration during cholangitis

Cholangiopathies such as primary sclerosing cholangitis (PSC) cause damage to the bile ducts with no effective cure. Reduction and impairment in the function of regulatory T cells (Tregs) occur in PSC. We investigate whether Tregs regulate bile duct regeneration and the dynamics of Treg turnover during bile duct injury. We use the transgenic Foxp3^GFPDTR model to mimic reduced Treg infiltration in PSC and show that Tregs mediate cholangiocyte response to biliary injury. Fate mapping of Tregs reveals that intrahepatic Tregs acquire a pro-inflammatory phenotype, even after interleukin-2 (IL-2)-mediated Treg expansion. Ox40L expression correlates with fibrosis in PSC patients. Enhancing Treg numbers through IL-2 complex administration and blocking Ox40 signaling simultaneously suppresses the inflammatory phenotype of Tregs and reduces bile duct damage and fibrosis. We demonstrate that bile duct regeneration can be enhanced by combining Treg-based therapy and targeting co-stimulatory molecules, such as Ox40L.