Abstract
The liver is an immunologically tolerant organ that is uniquely equipped to limit hypersensitivity to food-derived antigens and bacterial products through the portal vein and can feasibly accept liver allografts. The adaptive immune response is a major branch of the immune system that induces organ/tissue-localized and systematic responses against pathogens and tumors while promoting self-tolerance. Persistent infection of the liver with a virus or other pathogen typically results in tolerance, which is a key feature of the liver. The liver's immunosuppressive microenvironment means that hepatic adaptive immune cells become readily tolerogenic, promoting the death of effector cells and the “education” of regulatory cells. The above mechanisms may result in the clonal deletion, exhaustion, or inhibition of peripheral T cells, which are key players in the adaptive immune response. These tolerance mechanisms are believed to be responsible for almost all liver diseases. However, optimal protective adaptive immune responses may be achieved through checkpoint immunotherapy and the modulation of hepatic innate immune cells in the host. In this review, we focus on the mechanisms involved in hepatic adaptive immune tolerance, the liver diseases caused thereby, and the therapeutic strategies needed to overcome this tolerance.
Highlights
As the largest organ in the body, the liver has a rich circulatory supply, receiving blood from both the hepatic artery and the portal vein
We focused on: (i) T cell dysfunction, including anergy, exhaustion, and apoptosis, (ii) the regulatory mechanisms involved in the induction of T cell dysfunction, (iii) the current understanding of the role of T cell dysfunction in liver disease, and (iv) the therapeutic strategies developed to counteract adaptive immune tolerance, to illustrate the complexity of and challenges related to liver-mediated adaptive immune tolerance
Based on the mechanisms involved in liver tolerance, the presence of dysfunctional adaptive immune cells and immunosuppressive regulatory cells is a hallmark of chronic liver disease, including chronic infections and hepatocellular carcinoma (HCC)
Summary
As the largest organ in the body, the liver has a rich circulatory supply, receiving blood from both the hepatic artery and the portal vein. A high level of exposure to these antigens endows the liver with a distinctive form of immune privilege. This so-called immunotolerance ensures that the liver does not mount a strong immune response against gastrointestinal tract-derived molecules and pathogens. This tolerance effect is evidenced by the fact that the liver readily accepts allografts, despite a major histocompatibility complex (MHC) mismatch, as seen early on in the pig model of transplantation [1]. Later studies have shown that the liver can accept subsequent non-hepatic allografts from the same donor by inducing systemic immune tolerance [2]. The hepatic immune tolerogenic environment is exploited by hepatitis viruses, parasites, and tumors and can lead to persistent infection and rapid cancer progression
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