Bidirectional Cross-Talk between Biliary Epithelium and Th17 Cells Promotes Local Th17 Expansion and Bile Duct Proliferation in Biliary Liver Diseases

Abstract

There is no effective treatment for autoimmune biliary diseases. Therefore, understanding their immunopathology is crucial. The biliary epithelial cells (BEC), expressing TLR-4, are constantly exposed to gut microbes and bacterial wall LPS, and in settings of inflammation, the immune infiltrate is dense within the peribiliary region of human liver. By dual immunohistochemistry, we affirm human intrahepatic T cell infiltrate includes CCR6 + CD4 + and AhR + CD4 + T cells with potential for plasticity to Th17 phenotype. Mechanistically, we demonstrate that Th1 and Th17 inflammatory cytokines and LPS enhance human primary BEC release of the CCR6 ligand CCL20 and BEC secretion of Th17-polarizing cytokines IL-6 and IL-1b. Cell culture assays with human BEC secretome showed that secretome polarizes CD4 T cells toward a Th17 phenotype and supports the survival of Th17 cells. BEC secretome did not promote Th1 cell generation. Additionally, we give evidence for a mutually beneficial feedback of the type 17 cell infiltrate on BEC, showing that treatment with type 17 cytokines increases BEC proliferation, as monitored by Ki67 and activation of JAK2-STAT3 signaling. This study identifies human BEC as active players in determining the nature of the intrahepatic immune microenvironment. In settings of inflammation and/or infection, biliary epithelium establishes a prominent peribiliary type 17 infiltrate via recruitment and retention and enhances polarization of intrahepatic CD4 cells toward Th17 cells via type 17 cytokines, and, reciprocally, Th17 cells promote BEC proliferation for biliary regeneration. Altogether, we provide new insight into cross-talk between Th17 lymphocytes and human primary biliary epithelium in biliary regenerative pathologies.

The Immunological Basis of Liver Allograft Rejection

“…The CXCR3 receptor has been shown to be critical for Th17 cell migration into the inflamed liver; the cells then home to portal tracts with particular tropism toward BEC expressing the CCR6 ligand CCL20 ( 52 ). Subsequent work has shown the active role of BEC in maintaining Th17 dominant differentiation via release of IL-6 and IL-1β, and the stimulation of BEC proliferation by Th17 cytokines ( 53 ). There appears to be a degree of plasticity between Th17 and Treg differentiation such that the two exist in a state of dynamic equilibrium; this has generated interest in the importance of these divergent populations in skewing the immune response toward rejection or tolerance (see below).…”

Immune system and cholangiocytes: A puzzling affair in primary biliary cholangitis

“…is increased in response to exposure to LPS. 180 The stasis of bile acids in the damaged bile ducts is also a relevant player in the progression of the disease. The therapeutic efficacy of the UDCA and the beneficial effect of Farnesoid X receptor agonist obethicolic acid support the important role of bile acids in PBC pathogenesis.…”

Antigen presentation, autoantibody production, and therapeutic targets in autoimmune liver disease

“…The presence of LPS or CpG stimulates the secretion of inflammatory cytokines, such as IL-1β, IL-6, IL-8, IFNγ, TNFα, GM-CSF and TGFβ, that support effector cell polarization, as well as the CCR6 ligand CCL20 . 123 , 124 Furthermore, activated BECs were shown to produce Th17-polarizing cytokines, and inflammatory infiltrates in diseased livers contain CCR6 + CD4 + and aryl hydrocarbon receptor (AhR) + CD4 + naïve T cells with the potential to differentiate into Th17 effector cells. 124 Furthermore, the binding of IgA antibodies to glycoprotein 2 (α−GP2 antibodies) is associated with PSC and indicate large bile duct involvement, increased risk for cholangiocarcinoma, and mortality.…”