Regulatory T Cells in Autoimmune Hepatitis: Unveiling Their Roles in Mouse Models and Patients

Abstract

Autoimmune hepatitis (AIH) is a severe and chronic liver disease, and its incidence has increased worldwide in recent years. Research into the pathogenesis of AIH remains limited largely owing to the lack of suitable mouse models. The concanavalin A (ConA) mouse model is a typical and well-established model used to investigate T cell-dependent liver injury. However, ConA-induced hepatitis is acute and usually disappears after 48 h; thus, it does not mimic the pathogenesis of AIH in the human body. Several studies have explored various AIH mouse models, but as yet there is no widely accepted and valid mouse model for AIH. Immunosuppression is the standard clinical therapy for AIH, but patient side effects and recurrence limit its use. Regulatory T cells (Tregs) play critical roles in the maintenance of immune homeostasis and in the prevention of autoimmune diseases, which may provide a potential therapeutic target for AIH therapy. However, the role of Tregs in AIH has not yet been clarified, partly because of difficulties in diagnosing AIH and in collecting patient samples. In this review, we discuss the studies related to Treg in various AIH mouse models and patients with AIH and provide some novel insights for this research area.

Keywords: autoimmune hepatitis; cytochrome P450 2D6; mouse model; regulatory T cell; treatment.

Figure 1

Characteristic features of type 2 AIH in an improved mouse model. (A) Chronic liver inflammation (interface hepatitis) and characteristic pathological features (rosettes and lymphocytes invasion) are shown. The red arrow indicates the hepatocyte. (B) Sirius red staining showing the fibrosis in a mouse liver. The red color indicates collagenous fibers. (C) Stained autoantibodies from the plasma of AIH mice.

Figure 2

A summary of AIH mouse models. The mouse models are divided into two categories; one is based on a T cell-related mechanism and the other is based on an autoantigen- or liver antigen-related mechanism. The ConA mouse model is the most widely used mouse model to investigate acute T cell-mediated liver injury. Transgenic mice combined with T cell adoptive transfer also provides a method to establish an AIH mouse model. Some transgenic or gene knockout mice can develop spontaneous AIH-like disease. Treg depletion may also function as a potential method to induce AIH in mice. Transfecting the human autoantigen CYP2D6 or FTCD from type 2 AIH into mice may simulate the initiation process of type 2 AIH in humans to establish a chronic type 2 AIH mouse model. S-100, a supernatant of syngeneic liver homogenate, has also been used to induce AIH in mice. The expression of transgenic IL-2 in hepatocytes causes loss of tolerance of hepatocellular antigens, leading to chronic type 1 AIH-like disease in mice. Transfection HLA-DR3 or HLA-DR4 transgenic mice with the non-obese -diabetic background with a plasmid containing CYP2D6 and FTCD can also induce AIH.

Figure 3

Interaction between Tregs and other cells in AIH. The network shows the interaction of Tregs with other cells as well as the down-regulation of important inhibitory molecules and cytokines in Tregs of patients with AIH. The dotted lines represent the reported decreased regulation in AIH. CD8+ T cells, Th17 cells, Th22 cells, and Th1 cells contribute to inflammatory liver injury in AIH; these cells, are suppressed by Tregs. LSECs and NK cells contribute to the expansion of Tregs while HSCs can enhance the suppressive function of Tregs in AIH. Th17 is reported to inhibit Treg through IL-17A. IL-33 can enhance the expression of ST2 on the surface of Treg, thereby regulating the pro-inflammatory ILC2s in immune-mediated hepatitis.