Mechanisms of Immune Tolerance in Liver Transplantation-Crosstalk Between Alloreactive T Cells and Liver Cells With Therapeutic Prospects

Abstract

Liver transplantation (LTx) is currently the most powerful treatment for end-stage liver disease. Although liver allograft is more tolerogenic compared to other solid organs, the majority of LTx recipients still require long-term immune suppression (IS) to control the undesired alloimmune responses, which can lead to severe side effects. Thus, understanding the mechanism of liver transplant tolerance and crosstalk between immune cells, especially alloreactive T cells and liver cells, can shed light on more specific tolerance induction strategies for future clinical translation. In this review, we focus on alloreactive T cell mediated immune responses and their crosstalk with liver sinusoidal endothelial cells (LSECs), hepatocytes, hepatic stellate cells (HSCs), and cholangiocytes in transplant setting. Liver cells mainly serve as antigen presenting cells (APCs) to T cells, but with low expression of co-stimulatory molecules. Crosstalk between them largely depends on the different expression of adhesion molecules and chemokine receptors. Inflammatory cytokines secreted by immune cells further elaborate this crosstalk and regulate the fate of naïve T cells differentiation within the liver graft. On the other hand, regulatory T cells (Tregs) play an essential role in inducing and keeping immune tolerance in LTx. Tregs based adoptive cell therapy provides an excellent therapeutic option for clinical transplant tolerance induction. However, many questions regarding cell therapy still need to be solved. Here we also address the current clinical trials of adoptive Tregs therapy and other tolerance induction strategies in LTx, together with future challenges for clinical translation from bench to bedside.

Keywords: alloreactive T cells; crosstalk; liver cells; liver transplantation; tolerance induction.

Figure 1

Schematic illustration of three alloantigen recognition pathways. (A) Direct recognition of alloantigen: allograft antigen-presenting cells (APCs) present intact alloantigen directly to host T cells. (B) Indirect recognition of alloantigen: host APCs process and present the allograft-derived peptides to host T cells, mainly CD4 T cells. (C) Semi-direct recognition way: host APCs, mainly dendritic cells (DCs), acquire graft MHC molecules, which is called cross-dressing, and present the peptide directly to host T cells.

Figure 2

Crosstalk between alloreactive T cells and LSECs. LSECs constitute a unique vascular bed with fenestrae organized in sieve plates without basal membrane in the liver. They are the most powerful scavenger system by expression of pattern recognition receptors (PRRs), notably the mannose receptor (MR). On one hand, LSECs process and transfer the MHC-I to the naïve CD8 T cells, which is called “cross-dressing.” This priming process upregulates expression of the co-inhibitory molecule B7-H1(PDL1) on LSECs, whereas the expression of co-stimulatory molecule CD80/CD86 is not changed, thus the binding leads to the apoptosis of the alloreactive CD8 T cells. The LSECs induced tolerance is also highly correlated with antigen load and the strength of TCR stimulation. On the other hand, LSECs also prime naïve CD4 T cells with expression of MHC-II, especially under the inflammatory conditions, but fail to stimulate the proliferation of these cells due to the low expression of co-stimulatory molecules. LSECs also regulate the fate of naïve CD4 T cell differentiation within the liver graft. They suppress the differentiation of Th1 and Th17 cells but favor the enrichment of immune suppressive Th2 and Tregs, which promote the allograft tolerance.

Figure 3

Crosstalk between alloreactive T cells and hepatocyte, HSCs, cholangiocytes. The survived lymphocytes from LSECs immune surveillance can transmigrate across the LSECs line to crosstalk with hepatocytes. The paracrine factors secreted by hepatocytes also accelerate the recruitment of lymphocytes. Hepatocytes mainly serve as non-professional APCs with expression of MHC-I to interact with CD8 T cells under physiological conditions while expression of MHC-II is also inducible under inflammatory condition especially in the presence of IFNγ. Interaction of HSCs with activated alloreactive T cells mainly lead to apoptosis of these T cells due to the low MHC-I expression. Expression of MHC-I like molecule CD1d on cholangiocytes can activate NKT cells and mediate inflammation in the bile ducts.