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.
Highlights
Liver transplantation (LTx) is currently the most powerful treatment for end-stage liver disease
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
As alloreactive T cells or memory T cells mediated rejection represents a major hurdle to successful transplant tolerance induction, in this review, we mainly focus on the crosstalk between alloreactive T cells and liver cells in the transplant setting together with potential therapeutic prospects for tolerance induction
Summary
Liver transplantation (LTx) is currently the most powerful treatment for end-stage liver disease. Indirect recognition of alloantigen is considered to be related with both acute and chronic transplant rejection By this way, alloantigen is internalized and processed by host APCs into peptide antigens, which are further presented with host MHC molecules and thereby recognized by the TCR repertoire of host T cells (Figure 1B). Through the semi-direct recognition way, the host DCs acquire expression of the graft MHC molecule, which is called cross-dressing of the host DCs, represent the graft MHC-antigen complex as intact alloantigen to the host T cells without further processing (Figure 1C) This phenomenon was observed by Ono et al [33] that in a mice LTx model, graft interstitial DCs decreased rapidly post LTx, they were replaced by host DCs, which peaked at day 7 and persisted indefinitely.
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