The Role of Diverse Liver Cells in Liver Transplantation Tolerance

Abstract

Liver transplantation is the ideal treatment approach for a variety of end-stage liver diseases. However, life-long, systemic immunosuppressive treatment after transplantation is required to prevent rejection and graft loss, which is associated with severe side effects, although liver allograft is considered more tolerogenic. Therefore, understanding the mechanism underlying the unique immunologically privileged liver organ is valuable for transplantation management and autoimmune disease treatment. The unique hepatic acinus anatomy and a complex cellular network constitute the immunosuppressive hepatic microenvironment, which are responsible for the tolerogenic properties of the liver. The hepatic microenvironment contains a variety of hepatic-resident immobile non-professional antigen-presenting cells, including hepatocytes, liver sinusoidal endothelial cells, Kupffer cells, and hepatic stellate cells, that are insufficient to optimally prime T cells locally and lead to the removal of alloreactive T cells due to the low expression of major histocompatibility complex (MHC) molecules, costimulatory molecules and proinflammatory cytokines but a rather high expression of coinhibitory molecules and anti-inflammatory cytokines. Hepatic dendritic cells (DCs) are generally immature and less immunogenic than splenic DCs and are also ineffective in priming naïve allogeneic T cells via the direct recognition pathway in recipient secondary lymphoid organs. Although natural killer cells and natural killer T cells are reportedly associated with liver tolerance, their roles in liver transplantation are multifaceted and need to be further clarified. Under these circumstances, T cells are prone to clonal deletion, clonal anergy and exhaustion, eventually leading to tolerance. Other proposed liver tolerance mechanisms, such as soluble donor MHC class I molecules, passenger leukocytes theory and a high-load antigen effect, have also been addressed. We herein comprehensively review the current evidence implicating the tolerogenic properties of diverse liver cells in liver transplantation tolerance.

Keywords: T cell; allograft; hepatic microenvironment; liver transplantation; tolerance.

Figure 1

Mechanisms of tolerogenic hepatic microenvironment. The liver sinusoids are lined by a thin layer of fenestrated LSECs and lack organized basal lamina, which facilitate the passage of blood plasma to the underlying hepatocytes. Microvilli of hepatocytes extend into the space of Disse, existing between sinusoids and hepatocytes. The oxygenated arterial and nutrient- rich portal-venous blood undergoes confluence and runs through the liver sinusoids, carrying pathogens, toxins and harmless dietary antigens from the gut. The liver is highly enriched in both innate and adaptive immune cells, such as LSECs, KCs, DCs, HSCs, NK cells, NKT cells, and T cells. The unique liver microenvironment, with its slow blood flow and fenestrated endothelium in the narrow hepatic sinusoids, permits the continuous functional interaction between circulating naive T cells and the diverse hepatic-resident immobile non-professional APCs, such as hepatocytes, LSECs, KCs, DCs, and HSCs. This makes the liver the only non-lymphoid organ that can prime naïve T cell locally. These cells contribute to the liver tolerance through direct cell-cell interaction signaling by surface inhibitory molecules, as well as immunosuppressive milieu through secretory factors. The hepatocytes could also release massive amounts of soluble MHC class I molecules and destroy activated CD8⁺ T cells through “suicidal emperipolesis” mechanism. HSC, hepatic stellate cell; LSEC, liver sinusoidal endothelial cell; DC, dendritic cell; NK, natural killer cell; NKT, natural killer T cell; KC, Kupffer cell; IL-10, interleukin (IL)-10; TGF-β, transforming growth factor (TGF)-β; LSECtin, LSEC C-type lectin; MHC-I, major histocompatibility complex class I; PD-L1, programmed death ligand 1; FasL, Fas ligand; LPS, lipopolysaccharide; IL-27, interleukin (IL)-27; 15d-PGJ2, 15-Deoxy-Delta-12,14-prostaglandin J2; ARG1, Arginase-1; APC, Antigen-presenting cell; PGE2, Prostaglandin E2.

Figure 2

The hypothesis of NK cells in liver transplantation tolerance. In the liver, donor hepatic NK cells promote tolerance, possibly by directly killing recipient immune cells including activated T cells and recipient immature DCs recruited to the allograft, which limited the immune rejection responses. Recipient NK cells would switch to a tolerant phenotype in the tolerogenic hepatic microenvironment. In the secondary lymphoid organs, recipient NK cells kill donor passenger DCs, thereby limiting the activation of T cells by the direct pathway, but favoring the indirect pathway-primed alloreactive T cell response, which contributes to tolerance induction. DC, dendritic cell; NK, natural killer cell; APC, Antigen-presenting cell.

Figure 3

The fate of T cells in liver tolerance. The unique liver microenvironment determines the fate of T cells after activation. T cells were primed by DCs in secondary lymphoid organs or diverse hepatic-resident immobile non-professional APCs in the liver, such as hepatocytes, LSECs, KCs, and HSCs. They are insufficient to optimally prime T cells, which lead to the removal of alloreactive CTLs and suppress the differentiation of proinflammatory Th1 and Th17 cells but favor the skewing of immunosuppressive Th2 and Tregs. The liver is also referred as the graveyard of T cells, suggesting the specific ability of the liver to destroys T cells. Activated T cells would largely eliminate through clonal deletion, clonal anergy, apoptosis, “suicidal emperipolesis,” NK cell killing and T cell exhaustion, thus leading to liver tolerance. HSC, hepatic stellate cell; LSEC, liver sinusoidal endothelial cell; DC, dendritic cell; NK, natural killer cell; CTL, cytotoxic T lymphocyte; KC, Kupffer cell; Th1, T helper cell 1; Th2, T helper cell 2; Th17, T helper cell 17; Treg, Regulatory T cell; PD-L1, programmed death ligand 1; FasL, Fas ligand; APC, Antigen-presenting cell.