Immune tolerance in liver disease

Abstract

Liver tolerance is manifest as a bias toward immune unresponsiveness, both in the context of a major histocompatibility complex-mismatched liver transplant and in the context of liver infection. Two broad classes of mechanisms account for liver tolerance. The presentation of antigens by different liver cell types results in incomplete activation of CD8(+) T cells, usually leading to initial proliferation followed by either clonal exhaustion or premature death of the T cell. Many liver infections result in relatively poor CD4(+) T-cell activation, which may be because liver antigen-presenting cells express a variety of inhibitory cytokines and coinhibitor ligands. Poor CD4(+) T-cell activation by liver antigens likely contributes to abortive activation, exhaustion, and early death of CD8(+) T cells. In addition, a network of active immunosuppressive pathways in the liver is mediated mostly by myeloid cells. Kupffer cells, myeloid-derived suppressor cells, and liver dendritic cells both promote activation of regulatory T cells and suppress CD8(+) and CD4(+) effector T cells. This suppressive network responds to diverse inputs, including signals from hepatocytes, sinusoidal endothelial cells, and hepatic stellate cells.

Conclusion: Though liver tolerance may be exploited by pathogens, it serves a valuable purpose. Hepatitis A and B infections occasionally elicit a powerful immune response sufficient to cause fatal massive liver necrosis. More commonly, the mechanisms of liver tolerance limit the magnitude of intrahepatic immune responses, allowing the liver to recover. The cost of this adaptive mechanism may be incomplete pathogen eradication, leading to chronic infection.

Figure 1

Immunosuppressive circuits mediated mainly through liver myeloid cells. Kupffer cells may endocytose fragments of damaged hepatocytes, which convey TGF-β1 and cause the Kupffer cells to secrete IL-10. This acts in an autocrine manner to lead to Kupffer cells inducing a variety of immunosuppressive mechanism, both suppressing effector T cells and promoting T-reg cells. One of these, IDO, also directly responds to IFN-γ from activated effector T cells, creating a negative feedback loop. Healthy hepatocytes secrete HGF, which promotes MDSCs, while hepatic stellate cells secrete retinol and TGF-β1, promoting T-reg cell activation in the presence of DCs. Thus T cell immunity is suppressed both directly by diverse non-parenchymal cells, and also indirectly through mechanisms that activate T-reg cells.