The Role of Regulatory CD4 T Cells in Maintaining Tolerance in a Mouse Model of Autoimmune Hepatitis

Abstract

BackgroundThe role of regulatory CD4 T cells (Treg) in immune-mediated liver disease is still under debate. It remains disputed whether Treg suppress T cell-mediated hepatitis in vivo and whether hepatic regulatory T cells are functional in patients with autoimmune hepatitis.MethodsWe used TF-OVA mice, which express ovalbumin in hepatocytes, to investigate the impact of Treg in a model of autoimmune hepatitis. Treg isolated from inflamed livers of TF-OVA mice were tested for their functionality in vitro. By employing double transgenic TF-OVAxDEREG (DEpletion of REGulatory T cells) mice we analyzed whether Treg-depletion aggravates autoimmune inflammation in the liver in vivo.ResultsCD25+Foxp3+ CD4 T cells accumulated in the liver in the course of CD8 T cell-mediated hepatitis. Treg isolated from inflamed livers were functional to suppress CD8 T-cell proliferation in vitro. Depletion of Treg in TF-OVAxDEREG mice dramatically amplified T cell-mediated hepatitis. Repeated administration of antigen-specific CD8 T cells led to a second wave of inflammation only after depletion of Treg.ConclusionOur data add to the evidence for an important role of Treg in autoimmune hepatitis and show that Treg reduce the severity of T-cell mediated hepatitis in vivo. They constitute a key immune cell population that actively maintains a tolerogenic milieu in the liver and protects the liver against repeated inflammatory challenges.

Crosstalk between type II NKT cells and T cells leads to spontaneous chronic inflammatory liver disease

“…Several studies have suggested that impaired T reg function is responsible for over-activation of CD4 + and CD8 + T cells, which can lead to a breakdown in tolerance to liver antigens and a progression towards liver disease [36, 37]. Here, we showed that type II NKT cells may also play a role in the establishment of AIH.…”

The Imbalance between Foxp3+Tregs and Th1/Th17/Th22 Cells in Patients with Newly Diagnosed Autoimmune Hepatitis

“…In addition to effector T cells, Tregs are important regulators of immune tolerance and inflammation response. In this study, we found lower levels of Tregs in AIH patients and in EAH mice in a time-dependent manner, which were consistent with previous studies [ 18 , 32 , 33 ] but were different from another report [ 19 ]. Conflicting results may be due to differences in methodology, or detection markers of the definition of Tregs, because Moritz et al considered CD4 + CD25 high CD127 low FoxP3 + T cells as Tregs in their study.…”

Environmental peer pressure: CD4+ T cell help in tolerance and transplantation

“…CD4 1 T cell fate and effector functions are dictated by integration of environmental cues and costimulatory properties of APCs. The inflammatory and autoimmune manifestations (3,12,(30)(31)(32) of liver disease suggest that the physiologic microenvironment critically contributes to systemic tolerance; perturbations can have deleterious consequences. Alterations in the liver microenvironment during fibrosis can facilitate activation of typically hyporesponsive liver-resident APCs, resulting in enhanced T cell priming.…”

“…Although pretransplant indicators of graft acceptance rates are not well defined, there is evidence that immune responses within the liver may contribute to systemic tolerance of foreign antigens—including allografts . Moreover, perturbations within the liver microenvironment, such as chronic fibrosis, can manifest extrahepatically as inflammatory and autoimmune disorders, largely T cell–mediated phenomena . Here, we will review the influence of the liver microenvironment particularly on CD4 + T cell subset help and associated alterations during liver disease and how it can contribute to breaks in tolerance.…”

“…(28,29) Moreover, perturbations within the liver microenvironment, such as chronic fibrosis, can manifest extrahepatically as inflammatory and autoimmune disorders, largely T cell-mediated phenomena. (3,12,(30)(31)(32) Here, we will review the influence of the liver microenvironment particularly on CD4 1 T cell subset help and associated alterations during liver disease and how it can contribute to breaks in tolerance. Overall, a better understanding of the role of the intrahepatic microenvironment in transplant outcomes will inform clinical decisions surrounding transplantation.…”