Regulatory T Cells in Hepatic Immune Tolerance and Autoimmune Liver Diseases

Abstract

Regulatory T cells (Tregs) have a profound ability to control immune responses. A majority of Tregs are derived from the thymus; yet a substantial Treg fraction is derived from the periphery. The liver seems to be an important source of peripherally derived Tregs. Indeed, the liver's well-known ability to induce immune tolerance is at least partly based on hepatic Treg generation. With recently developed tools to deliver antigens to tolerance-inducing liver cells, it is now possible to harness liver-derived Tregs for specific control of unwanted immune responses. Indeed, the selective delivery of autoantigens to liver sinusoidal endothelial cells could induce autoantigen-specific Tregs in vivo, providing effective treatment of autoimmune disease. Owing to the fundamental role Tregs play in controlling immune responses, an impairment of Tregs seems to be a plausible explanation for the development of autoimmune diseases, for example, in the liver. However, the actual role of Treg impairment in autoimmune liver diseases, such as autoimmune hepatitis (AIH), remains controversial. Major obstacles for clarifying the role of Tregs in autoimmune liver diseases are related to the difficulty to identify human Tregs unambiguously and to the difficulty to identify those Tregs and effector T cells that specifically recognize disease-driving autoantigens. However, even if AIH turned out to be a disease that is not driven by Treg impairment, Treg-based therapies for autoimmune liver diseases might still be effective, provided the Tregs for therapeutic use recognize the relevant antigens.

The Crosstalk between Fat Homeostasis and Liver Regional Immunity in NAFLD

“…Liver disease (viral hepatitis, liver fibrosis, fatty liver, alcoholic liver, drug-induced liver damage and cirrhosis, and liver cancer), relating to liver immune cell disorders, is one of the reasons for high mortality in some countries and regions of the world [12–14]. Nonalcoholic fatty liver disease (NAFLD) is the most common cause of liver disease, the primary feature of which is simple steatosis caused by accumulation of liver triglycerides (TG), followed by nonalcoholic steatohepatitis (NASH) with inflammation, fibrosis, and liver damage, eventually developing into cirrhosis and hepatocellular carcinoma (HCC).…”

Regulatory T Cell and Forkhead Box Protein 3 as Modulators of Immune Homeostasis

“…Selective autoantigen stimulation is known to lead to Treg generation in sinusoidal endothelial cells in vivo , which is considered to be an effective anti-autoimmune mechanism (149). In a mouse model of primary biliary cirrhosis, which is similar to the human disease, sf mice were used to demonstrate that abnormal Treg function is accompanied by exacerbation of CD8 + T cell-mediated bile duct autoreactive damage (150).…”

Inhibition of lipopolysaccharide-induced inflammation via the protective role of T regulatory cells in the fetal liver in a late-pregnancy preterm mouse model

“…Tregs have a strong ability to initiate immune responses (4). Tregs are a subset of CD 4 + cells that sustain peripheral immune homeostasis by inhibiting a range of inappropriate immune responses and establishing the balance between immune tolerance and activation (5). Treg development is maintained by Foxp3, which is responsible for encoding a transcription factor that is genetically defective in autoimmune and inflammatory syndromes in mice and humans (6).…”

“…Tregs have a strong ability to initiate immune responses ( 4 ). Tregs are a subset of CD 4 + cells that sustain peripheral immune homeostasis by inhibiting a range of inappropriate immune responses and establishing the balance between immune tolerance and activation ( 5 ).…”