Interleukin 2 Promotes Hepatic Regulatory T Cell Responses and Protects From Biliary Fibrosis in Murine Sclerosing Cholangitis

Abstract

In the multidrug resistance protein 2 (Mdr2) mouse model, low phospholipid bile instigates biliary epithelial injury, sterile inflammation, and fibrosis, thereby recapitulating disease mechanisms implicated in biliary atresia (BA) and primary sclerosing cholangitis. We hypothesize that T lymphocytes contribute to the biliary injury and fibrosis in murine sclerosing cholangitis (SC) and that they are susceptible to suppression by regulatory T cells (Tregs). In juvenile Mdr2 mice, intrahepatic CD8+ lymphocytes were expanded, and contraction of intrahepatic Tregs coincided with rising serum alanine transferase and alkaline phosphatase (ALP) levels between days 14-30 of life. Antibody-mediated depletion of intrahepatic CD8+ lymphocytes during that time reduced ALP levels and the expression of osteopontin (Opn), a pro-fibrogenic cytokine. Depletion of intrahepatic Tregs with anti-CD25 antibody between days 7-30 increased intrahepatic CD8+ T cells, Opn expression, and fibrosis. Conversely, expansion of intrahepatic Tregs with interleukin 2/anti-interleukin 2 immune complexes (IL-2c) downregulated hepatic expression of Opn and Tnf, reduced frequency of intrahepatic CD8+ lymphocytes, and diminished biliary injury and fibrosis. Treatment with IL-2c upregulated hepatic Treg expression of CD39, an ectonucleotidase capable of hydrolyzing pro-inflammatory adenosine triphosphate. In vitro, Tregs expressing CD39 suppressed the proliferation of hepatic CD8+ lymphocytes from Mdr2 mice more efficiently than those lacking CD39. In infants with BA, infiltration of interlobular bile ducts with CD8+ cells was associated with biliary expression of Opn and its transcription was negatively correlated with mRNA expression of Treg-associated genes. Conclusion: Hepatic CD8+ T lymphocytes drive biliary injury and fibrosis in murine SC. Their proliferation is controlled by hepatic Tregs through the purinergic pathway, which is responsive to IL-2c, suggesting that Treg-directed low-dose Il-2 treatment may be considered as therapy for SC.

T Cells in Fibrosis and Fibrotic Diseases

“…Depletion or restoration of Treg cells may become a viable approach in controlling fibrosis in this case. In contrast, in Mdr2 (Abcb4) deficient mice with sclerosing cholangitis, a low dose of IL-2 treatment diminishes biliary injury and fibrosis by the expansion of intrahepatic Tregs ( 44 ).…”

The role of the CD39–CD73–adenosine pathway in liver disease

“…With the in‐depth study of the pathogenesis of liver fibrosis, in recent years, it has been found that the CD39–CD73–adenosine pathway has anti‐inflammatory effects in the short term, but in certain cases, it may also promote liver fibrosis through repetitive signaling in defined circumstances (Ferrari et al, 2016). Indeed, Tregs expressing CD39 inhibited the proliferation of hepatic CD8+ T lymphocytes, and CD39 expressed by macrophages can protect from biliary liver injury and fibrosis, while CD39 knockout macrophages, could aggravate liver fibrosis (Peng et al, 2017; Rothweiler et al, 2019; Taylor et al, 2018). Similarly, CD73 knockdown increased cell migration and collagen I expression (crucial features of the fibrogenic process) in HSC lines, and CD73 expression was reduced in activated HSCs (Andrade et al, 2011, 2008).…”

Low-Dose IL-2 Therapy in Transplantation, Autoimmunity, and Inflammatory Diseases

“…Hepatic CD8 1 T lymphocytes drive biliary injury and fibrosis in murine sclerosing cholangitis. Their proliferation is controlled by hepatic Tregs through the purinergic pathway, which is responsive to IL-2c, suggesting Treg-directed lowdose IL-2 as a potential therapy for sclerosing cholangitis (53). Finally, in transfusion-related acute lung injury (TRALI), daily i.p.…”