Liver-Mediated Adaptive Immune Tolerance

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.

Keywords: T cell dysfunction; immune regulation; innate cell dysfunction; liver diseases; liver tolerance; liver-draining lymph node.

Figure 1

Mechanisms involved in liver-mediated adaptive immune tolerance. The diagram outlines that the liver acts as a “graveyard” or killing field for activated T cells, leading to the apoptosis of activated T cells through clonal deletion, clonal anergy, clonal deviation, or exhaustion (a). Alternatively, the liver can act as a school to educate T cells, which means that T cells can be subjected to regulation by liver APCs, including dendritic cells (DCs), hepatocytes, Kupffer cells, liver sinusoidal endothelial cells (LSECs), regulatory T cells (Tregs), and NK cells, and cytokines like IL-10, TGF-β, and IFN-γ, which promote T cell dysfunction (b). Furthermore, dysfunctional T cells may be induced by the liver-draining LN environment through antigen presentation. The liver-draining portal and celiac lymph nodes (LNs) play an important role in regulating hepatic immune tolerance (c). Moreover, mild or absent signs of liver inflammation, as evidenced by reduced levels of IFN-α, IL-12, and TNF-α cytokines, are also associated with the scenario of liver tolerance.

Figure 2

Potential strategies for reversing adaptive immune tolerance in chronic infection or cancer of the liver. During chronic pathogenic infection or tumorigenesis in the liver, dysfunctional adaptive immune responses may be associated with dysfunctional antigen-presenting cells (APCs), natural killer (NK) cell subsets, or T cells. Moreover, mild or absent inflammation may also result in a failure to clear/restrict pathogenic infection or tumor formation. Potential strategies for reversing adaptive tolerance might include checkpoint inhibitor blockade, modulation of specific immune subsets, intrahepatic myeloid-cell aggregates for T cell expansion (iMATES) formation, or liver-draining lymph nodes (LNs) to shape antigen presentation. As a result of these interventions, the restoration of effective immune responses may help to clear or restrict pathogenic infections or tumors with effective T cell function, efficient regulation by specific APC or NK cell subsets, and moderate liver inflammation.