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.

Immunology of hepatic diseases during pregnancy

“…Being continuously exposed to harmless food and microbial antigens from the intestine that are supplied to the liver via the portal vein, the liver rather responds with immunosuppression than with immune activation [19][20][21][22]. This socalled liver tolerance effect has been demonstrated most impressively in experimental transplantation settings, which not only demonstrated immune privilege towards the liver allograft but also towards co-transplanted organs from the same donor [23].…”

Adeno-Associated Virus Gene Therapy for Liver Disease

“…96,97 Mouse LSECs function as a specialized form of antigen-presenting cell and express receptors that promote antigen uptake, including the mannose receptor and the scavenger receptor, and molecules that promote antigen presentation, including CD40, CD80, and CD86. Although mouse LSECs can prime both CD4 and CD8 T cells, the most common consequence of this is tolerance induction versus activation.…”

Dynamics of antigen presentation to transgene product-specific CD4+ T cells and of Treg induction upon hepatic AAV gene transfer

“…The architecture and composition of liver provide an environment that often promotes immune tolerance. 41 For example, APC residing in sinusoids such as KCs and LSEC allow for antigen presentation to T cells present in the blood. The liver also contains a larger number of plasmacytoid DCs than other organs.…”