Adaptive immunity in the liver

Abstract

The anatomical architecture of the human liver and the diversity of its immune components endow the liver with its physiological function of immune competence. Adaptive immunity is a major arm of the immune system that is organized in a highly specialized and systematic manner, thus providing long-lasting protection with immunological memory. Adaptive immunity consists of humoral immunity and cellular immunity. Cellular immunity is known to have a crucial role in controlling infection, cancer and autoimmune disorders in the liver. In this article, we will focus on hepatic virus infections, hepatocellular carcinoma and autoimmune disorders as examples to illustrate the current understanding of the contribution of T cells to cellular immunity in these maladies. Cellular immune suppression is primarily responsible for chronic viral infections and cancer. However, an uncontrolled auto-reactive immune response accounts for autoimmunity. Consequently, these immune abnormalities are ascribed to the quantitative and functional changes in adaptive immune cells and their subsets, innate immunocytes, chemokines, cytokines and various surface receptors on immune cells. A greater understanding of the complex orchestration of the hepatic adaptive immune regulators during homeostasis and immune competence are much needed to identify relevant targets for clinical intervention to treat immunological disorders in the liver.

Figure 1

A schematic diagram of the functional changes and some of the influential factors in chronic HBV/HCV infections. The ability of CD8 T cells (Tc) to clear HBV/HCV is inhibited by various factors. HBV and HCV are inhibited by the virus-specific Tc. Both CD4 Treg and CD8 Treg cells suppress Tc function and promote the switch of the Tc cells from the active state in acute phase to the exhausted state in the chronic phase. CD4 Th cells are indispensable for the activation and maintenance of Tc immunity against HBV/HCV. However, Th cells can also be suppressed and exhausted similarly to Tc cells. MDSCs are another factor that facilitates Tc exhaustion. Increased expression of inhibitory protein receptors (such as PD-1, CTLA-4, Tim-3, Bim and CD224) on Tc/Th cells contributes to their exhaustion. Therefore, treatments that block the interaction between these receptors and their ligands, and inhibit Treg functions are potential therapeutic strategies for chronic HBV/HCV infections.

Figure 2

Changes in the functions of the major adaptive immune cells in HCC. CD8 T cells, the primary HCC-specific killer and its helper CD4 CD25^─ Th cells are inhibited, whereas the inhibitory immune cells, including Treg cells, MDSCs and CD14⁺CTLA-4⁺ DCs, are increased in HCC patients. Moreover, the HCC cell itself can evade adaptive immune surveillance through several strategies, such as reduced expression of the HLA-I antigen and enhanced expression of PD-L1, the ligand of PD-1, which is expressed on the tumor-filtrating T cells and mediates T-cell suppression or apoptosis. These functional alterations of the T cells promote HCC occurrence and development.

Figure 3

A schematic representation of the interaction between adaptive immunocytes and cholangiocytes in PBC. Teffs, which include Th1, Th2, Th17 and Tfh cells, are, at least in part, over-activated by downregulated Treg cells. Cholangiocytes are both the victim and accomplice of the autoimmunity in PBC. Upon aberrant expression of HLA-II, cholangiocytes can act as APCs to promote adaptive autoimmunity in the liver. The expression of CX3CL1 contributes to recruiting T cells to the liver. CD40, CD80 and CD86 expressed on cholangiocytes activate Teffs. Furthermore, the cytokines and interleukins (such as IL-6, IL-8 and MCP-1) secreted by the cholangiocytes promote autoimmunity. Collectively, these factors will increase adaptive autoimmunity and cholangiocyte apoptosis in PBC.