Modulation of liver tolerance by conventional and nonconventional antigen-presenting cells and regulatory immune cells

Abstract

The liver is a tolerogenic organ with exquisite mechanisms of immune regulation that ensure upkeep of local and systemic immune tolerance to self and foreign antigens, but that is also able to mount effective immune responses against pathogens. The immune privilege of liver allografts was recognized first in pigs in spite of major histo-compatibility complex mismatch, and termed the "liver tolerance effect". Furthermore, liver transplants are spontaneously accepted with only low-dose immunosuppression, and induce tolerance for non-hepatic co-transplanted allografts of the same donor. Although this immunotolerogenic environment is favorable in the setting of organ transplantation, it is detrimental in chronic infectious liver diseases like hepatitis B or C, malaria, schistosomiasis or tumorigenesis, leading to pathogen persistence and weak anti-tumor effects. The liver is a primary site of T-cell activation, but it elicits poor or incomplete activation of T cells, leading to their abortive activation, exhaustion, suppression of their effector function and early death. This is exploited by pathogens and can impair pathogen control and clearance or allow tumor growth. Hepatic priming of T cells is mediated by a number of local conventional and nonconventional antigen-presenting cells (APCs), which promote tolerance by immune deviation, induction of T-cell anergy or apoptosis, and generating and expanding regulatory T cells. This review will focus on the communication between classical and nonclassical APCs and lymphocytes in the liver in tolerance induction and will discuss recent insights into the role of innate lymphocytes in this process.

Figure 1

Schematic representation of the microanatomy of the liver sinusoids and their cellular composition. The hepatocytes are separated from the sinusoidal blood flow by the liver sinusoidal LSECs that create the Space of Dissé and shield the hepatocytes from sinusoidal blood flow. Between the LSECs and the hepatocytes, hepatic HSCs are interspersed. In the sinusoidal lumen, KCs and passenger leukocytes are located. Note that T cells can form intimate contacts with microvilli from hepatocytes, but also LSECs or KCs, which enables priming of T cells in the liver. HSCs, hepatic stellate cells; KCs, Kupffer cells; LSECs, liver sinusoidal endothelial cells.

Figure 2

Electron microscopic analyses of liver sinusoids. (a) Transmission electron microscopic image of a lymphocyte (L) within the intrahepatic sinusoidal lumen (S); original magnification × 12 000; e=LSEC; H=hepatocyte. (b) Intrasinusoidal leukocyte, scanning microscopic image (s.e.m.); note that its cytoplasmic extensions exhibit a similar diameter compared with the sinusoidal fenestrations; original magnification × 10 000. (c) s.e.m. of microvilli from a hepatocyte (H) protruding into the sinusoidal lumen (S); original magnification × 40 000. (d) s.e.m. of LSECs; original magnification × 15 000. (e) Higher magnification s.e.m. picture, showing a liver sieve and visibility of the hepatocyte's microvilli underneath the endothelial layer; original magnification × 20 000. Note the absence of the basal lamina between the LSECs and hepatocytes. Reproduced from Warren et al. with permission.

Figure 3

Liver-mediated T-cell priming and hepatocyte-T-cell interactions as tools for tolerance induction. (a) and (b) depending on the antigen load and the density of ligands presented by hepatocytes, priming of T cells can result in either activation and expansion, and initiation of an effector response, when the antigen density is low, or (a) T-cell anergy and exhaustion are induced when the antigen-load is high (b). (c) An alternate mechanism to induce peripheral tolerance by hepatocyte-T-cell interaction is emperiopolesis, where autoreactive T cells are invading hepatocytes and are thus eliminated in the hepatocytic lysosomal compartments.

Figure 4

Differences in the outcome of T-cell priming between conventional APCs in the lymph nodes and nonconventional APCs, such as hepatocytes. (a) In secondary lymphoid organs, DC-mediated T-cell priming results in T-cell expansion and activation of their effector function. In the case of cytolytic T cells, naive CD8⁺ T cells expand after antigen-specific stimulation, exhibit prolonged survival indicated by up-regulated bcl-xL expression, express inflammatory cytokines such as IFN-γ and CD107a (LAMP1 as markers of their cytotoxic activity. Bcl-x_L is a member of the Bcl-2 family of apoptosis regulators and enhances apoptosis protection and prolongs survival. (b) Naive CD8⁺ T-cell priming in the liver by hepatocytes leads to death by neglect, a mechanism leading to premature death of T cells. This demonstrates that hepatocytes can induce antigen-specific activation and proliferation of naive CD8⁺ T cells independent of co-stimulatory signals; premature cell death of liver-primed T cells can be prevented by CD28 cross-linking. Death by neglect is a pivotal mechanism to induce peripheral tolerance to hepatic antigen recognition. (c) After ConA treatment, TGF-β and IL-10 are produced, and induce tolerance via Foxp3⁺ Treg induction; Treg-derived IL-10 and TGF-β also contribute to the upkeep of tolerance; (d) Hepatocytes express the Notch ligand Jagged-1 in inflammation after induction of ConA hepatitis; CXCR3⁺ Tregs are recruited to the liver by enhanced CXCL9/CXCL10 expression in ConA hepatitis, and are converted into IL-10⁺Foxp3⁺ Tregs, which also express Notch1. This conversion depends on the presence of IFN-γ. Bcl-2, B-cell lymphoma-2.