The liver is unique among transplanted organs with respect to its complex, and sometimes paradoxical, interaction with the host immune system. Early liver transplantation studies with outbred swine demonstrated that a significant percentage of recipients maintained their graft in the absence of immunosuppression.1 Subsequently, spontaneous liver allograft acceptance was also observed in transplants done in several allogeneic rat strain combinations and most allogeneic mouse strain combinations. Moreover, other experimental studies in rodents demonstrated that allogeneic liver transplantation provides immune “protection” against subsequent cardiac, kidney, pancreas, islet, and skin grafts from the same donor.1-7 Finally, in clinical transplantation there is increasing evidence, both anecdotal and documented, that some liver transplant recipients who cease taking immunosuppressive drugs maintain allograft function, suggesting robust tolerance is in place. Hence, the liver shows features of immune privilege. Nevertheless, the liver can display destructive immunologic processes since acute liver allograft rejection does occur in approximately 50% to 75% of liver transplant recipients, although in the majority of cases it is readily reversed with immunosuppressive approaches tailored to treat cellular rejection (covered in a separate CAQ corner). Whereas immune responses within the liver can effectively eliminate hepatotropic pathogens including hepatitis A, other liver pathogens such as hepatitis C persist and manage to avoid elimination by the immune system. Finally, a variety of autoimmune diseases with unknown etiologies target the liver, including primary biliary cirrhosis, primary sclerosing cholangitis, autoimmune hepatitis, and biliary atresia. Together, these observations underscore the enigmatic relationship between the liver and host immunity. In this article, we discuss the hepatic immune system, basic principles governing the host T-cell response to alloantigen following liver transplantation, experimental studies elucidating the cellular and molecular mechanisms of liver allograft rejection and tolerance, and immunologic perspectives of recent developments in clinical liver transplantation. Th, T helper cell; IL, interleukin; DC, dendritic cell; APCs, antigen-presenting cells; MHC, major histocompatibility complex; LSEC, liver sinusoidal endothelial cell; NK, natural killer; TCR, T-cell receptor; IFN, interferon; CTLA4, cytotoxic T lymphocyte associated antigen 4; Ig, immunoglobulin; ICOS, inducible costimulator; PD, programmed death; PDL, programmed death ligand; CTLs, cytotoxic T lymphocytes; FasL, Fas ligand; HLA, human leukocyte antigen. The primary role of the immune response is to protect the individual from invasion by infectious pathogens and to provide self-nonself discrimination. The coordination of an efficient immune response requires the recognition of pathogens and subsequent activation of immune cells and soluble mediators of immunity. The innate immune system, through its ability to rapidly limit the spread of infectious pathogens provides the speed component. In contrast, classical T cells provide the specificity, which requires days to weeks to develop. These discrete subsets function as part of a coordinated and complementary system, and their importance for host defense is seen in secondary responses in which speed and specificity are united in the form of immunological memory.8 Although graft rejection is mediated primarily by T cells, as indicated by the fact that skin grafted onto nude mice, which lack T cells, is not rejected, it is important to understand the division of labor by diverse cells comprising the immune system. Moreover, increasing evidence indicates that T cells also exert regulatory functions, favoring peripheral tolerance.9 Several subsets of CD4+ T cells with suppressive properties have been described, including naturally occurring CD4+CD25+ regulatory T cells, T regulatory type 1, and T helper (Th) type 3 cells.10 CD4+CD25+ regulatory T cells suppress the response of conventional T cells via a cell contact-dependent mechanism, whereas Th3 and T regulatory type 1 cells produce immunosuppressive cytokines, e.g., transforming growth factor-β and interleukin (IL)-10. Dendritic cells (DCs) are professional antigen-presenting cells (APCs) that are present in virtually all organs and provide a critical link between innate and adaptive immunity. The ability of DCs to process and present various types of antigens, including antigens derived from dead cells, is unmatched in the human body.11 Immature DCs express low levels of major histocompatibility complex (MHC) class II, adhesion, and costimulatory molecules, but their expression is dramatically upregulated during maturation in response to appropriate inflammatory stimuli.12 There is expanding evidence that liver-derived DCs can downregulate immune responses, hence inducing and maintaining peripheral T-cell tolerance.13 Furthermore, it has been hypothesized that following liver transplantation, the existence of large numbers of DCs within the donor liver that circulate and repopulate the recipient contributes to microchimerism.14 Because of its location and function, the liver is continuously exposed to diverse and large antigenic loads, including pathogens, toxins, and tumor cells, as well as dietary and commensal proteins.15 The liver must be actively immunocompetent and simultaneously control inappropriate inflammatory responses to dietary and other harmless antigens encountered in the portal circulation, thus being able to selectively induce immunity or tolerance to antigens.16 Hepatic suppression of sensitization to antigen absorbed by the portal system was demonstrated as early as 1967.17 The context in which antigen is presented to T cells determines whether the responding T cell is activated or tolerized. This includes the nature of the APC, the presence or absence of costimulatory molecules and the cytokine microenvironment.17 In particular, hepatic APCs have a constitutive ability to activate and induce tolerogenic responses in T cells.18 Liver sinusoidal endothelial cells (LSECs) have a unique immune phenotype, expressing markers typical of cells of myeloid lineage (CD1, CD4, CD11c), even though recent data suggest that these cells differentiate from hepatocyte progenitors.17 LSECs resemble immature DCs more than typical microvascular endothelial cells from other organs and seem to be a new type of organ-specific APCs.17 CD4+ T cells primed by antigen-presenting LSECs fail to differentiate toward effector Th1 cells but, instead, express high levels of immune suppressive IL-10. Moreover, antigen presentation to CD8 T cells by LSECs in vivo leads to their inability to respond to specific antigen upon restimulation.19 Taken together, these data implicate antigen presentation by LSECs—the only cells to have direct contact with immune cells passing through the liver—as a primary mechanism of systemic tolerance. Lymphocytes are broadly divided into B cells, T cells, and natural killer (NK) cells; whereas B and T cells possess clonotypic antigen receptors that confer specificity for diverse antigenic structures, NK cells possess multiple receptors that can detect conserved antigens or danger signals that mediate MHC-unrestricted cytolysis of susceptible tumor and virus-infected cells.15, 20 Golden-Mason and colleagues have documented an unusually high percentage of unconventional lymphoid cells in the liver that are rarely present in the blood, including NK cells, NKT cells expressing the γδ T-cell receptor (TCR) and the invariant Vα24JαQ TCR, and DCs.21, 22 Although the precise nature of the antigens recognized by these putative regulatory cells is currently unknown, CD1d (expressed on the surface of APCs [Kupffer cells] and hepatocytes23) has been shown to be a natural ligand for NKT cells.24 Figure 1 shows the relative proportions of the major lymphocyte subsets present in the healthy adult human liver as compared with the lymphocyte repertoire found in the peripheral blood (used with permission, from Doherty and O'Farrelly15). For example, NK (CD3−CD16+CD56+) cells represent 5% to 15% of the peripheral mononuclear cell population, but in the liver can comprise 45% of the lymphocyte population.25, 26 It has been suggested that these cells deliver a death signal to circulating recipient derived T cells that migrate through the liver after transplantation, contributing to tolerance.27 Thus, the adult human liver contains several populations of lymphocytes that exhibit rapid antigen-nonspecific cytotoxicity and regulatory cytokine secretion28; these cells play important roles in containment of tumor and viral infections, fibrosis development,29 and allograft rejection/tolerance. Distribution of lymphocyte subpopulations in healthy human blood and liver. (Adapted from Doherty and O'Farrelly.15) T lymphocytes can donor alloantigen through of In the direct host T lymphocytes molecules on In the host T lymphocytes donor in the context of molecules on recipient APCs for both in liver It is that the direct early and is a major in acute rejection since APCs expressing donor alloantigen rapidly from the graft and secondary lymphoid can T T cells primed through the direct have the ability to the allograft to mediate effector the of host T cells that can respond to alloantigen is than the of host T cells that can respond through the to presented in the context of The from donor alloantigen that is from graft or in the of the liver, from soluble class molecules, that are and presented by Thus, the direct be important in the classical form of acute the be important in an response that is by as a variety of are presented by T cells with specificity for readily in liver recipients the same it is that the is in immune since T cells with specificity shown to have regulatory function through of in The relative importance of the direct and in liver allograft rejection and tolerance to be and graft of In the T cells major histocompatibility molecules on donor antigen-presenting cells In the T cells alloantigen in the form of presented by recipient antigen-presenting cells among endothelial cells, T cells, and recipient antigen-presenting cells in allograft are by endothelial cells to the graft are also to efficient antigen-presenting dendritic cells that to to peripheral lymphoid organs for The dendritic cells and present donor via the to CD4+ T T cells, on the other are activated by donor endothelial cells and can endothelial cells or the and graft and with from T lymphocytes must but coordinated signals in to The signal is by the following recognition of on APCs and the signal is by the interaction of costimulatory molecules on the T cells and their on 1 in the absence of signal as in the liver, leads to a of T-cell or in which T cells can antigen through the but fail to a response upon with the antigen. Thus, there has been significant or as a to allograft costimulatory that are important in the of a T-cell response are and the T-cell costimulatory In is on of T cells and 50% of CD8 T In with of leads to of such as cellular and of The for and are found on a variety of APCs including B cells, and The constitutive expression of is than for on APCs, although expression is during The expression of and has been by and in human following was found on the majority of cells in all transplanted and in liver. was and was present only on liver but was present on of the cells in 45% of the transplanted expression not with the of acute T lymphocyte associated antigen is a that is upregulated upon T-cell activation to and Whereas a costimulatory signal to T cells, a signal that T-cell Because expression is following T-cell and it has a for than it has been that the function of is to or downregulate T-cell Thus, specific activation of function and tolerance but this has been by the lack of to deliver the The is a that is critical in is on APCs, including B cells, and but can also be on cells including endothelial cells, cells, and In contrast, is on T cells following and to a on NK cells, B cells, and CD8 T the costimulatory that has primarily been in the context of on T-cell function, function as by of class II, and expression and of cytokines, including The of these to the is to and T-cell responses to and of and expression in of liver recipients demonstrated an between expression of and but not in the graft during acute cellular was also on cells and sinusoidal in during rejection but not in liver or to the and have upon specific or soluble such as In the rat liver transplantation of the of transplantation, or of in with donor to graft of whereas of or donor approaches to deliver to liver have been with some of by or low to induce graft In contrast, the of and low in graft with most maintaining their graft of through vivo of to of rat liver and the of of also in rat liver allograft and donor specific The of and compared in a rat liver allograft to allograft but with was associated with biliary and endothelial cell compared with The was also shown to play a role in in or with hepatic and in a compared with control the and costimulatory have the of in transplantation, there is evidence that other also play important roles in there has been in new of the is following T-cell activation and cellular and cytokine The ligand for ICOS, is on B cells, and dendritic cells as well as including the The was to provide a costimulatory signal for cytokine although it is can also the of the Th1 cytokine a role in activation and also in of T regulatory is upon activation of T cells, with CTLA4, and contains an in the of cellular receptors that deliver a in to programmed death ligand and by Th1 and cytokines, is in the liver on cells and sinusoidal display a spontaneous of CD8 T cells in the Moreover, in the absence of T-cell activation to an form of experimental autoimmune hepatitis suggesting that a role in the of CD8 T cells in the liver Several of the tumor receptor of which are can also provide costimulatory signals to T These and The receptor is on and CD8 T cells following its is on activated B cells, and The receptor to be important in CD8 T-cell In contrast, primarily on T is T-cell costimulatory that has been in has been shown to the cell in response to and T cells comprise the major of and cells following soluble form of in the blood early was shown to be a and specific for acute rejection in In these costimulatory molecules are on T cells following activation and their relationship to is to be and to T-cell function in the context of or to provide their role in liver transplantation to be T cells have signals through the and the appropriate costimulatory molecules for and from or cell surface receptors for to effector effector T cells, be CD4+ or are of graft has on the of effector T cells from cells and T and this of of the immune of graft recipients in the The of effector in graft rejection is type and The relative importance of of these in graft rejection is to on a variety of including the the sensitization of the infections, and the immunosuppressive that are cytotoxic T lymphocytes specific for donor class can with the graft and through mechanisms that induce is a of cell death in liver allograft In the effector and the B to induce target cell is into the target cell in a process that the and of B into the target cell from cellular This leads to target cell death through in B are associated with acute liver allograft suggesting that this is following human liver The ligand is by Whereas is upon Fas is on lymphoid and including the liver. of Fas with or leads to of the death inducing complex in target cells, activation of and of a death signal that in The is to play an important role in a variety of hepatic and there is evidence that this is also during liver allograft more is by CD8 T cells as well as by T cells and NK cells and can also induce target cell there have been on the of in liver allograft type is by T cells specific for donor class to specific T cells a cytokine that can activation of and the subsequent of a variety of soluble These inflammatory mediators can the cellular response or can direct The presence of T cells in graft recipients can be in the type response in which peripheral blood mononuclear cells from graft recipients are into the or of The of following with specific alloantigen provides an of the of the the presence of regulatory in 3 including 1 liver transplant who but maintained graft In this peripheral blood mononuclear cells from the 3 response to donor but responses to antigens such as in the of responses be with to or transforming growth that these to maintaining specific for graft antigens can mediate graft through activation of the or through to receptors on effector cells and rejection by blood class or class are not to play a role in liver allograft a mechanism was in which against LSECs acute In this it was that against LSECs more observed in rejection than in Furthermore, the expression of on LSECs and T-cell transforming growth factor-β in a significant of the was not against human leukocyte antigen antigens, suggesting that other cellular are the target of these It has been a process to to the of specific effector and their in liver allograft It is to that T cells, CD8 T cells, and cells can be found in the liver during it is more to that of these cell types are actively in a destructive immune The of studies in experimental transplantation has that it is to or cell type that is for graft it that several and mechanisms are in that can to graft Moreover, the of of graft rejection by other cell types found within the inflammatory such as has been and be as The rat liver transplant has been in into the immunologic mechanisms that are following liver transplantation. In the the of liver transplantation is upon the strain as some combinations to acute cellular whereas to spontaneous tolerance. The strain combinations that in acute rejection the features of human liver allograft Thus, in the a and mononuclear cell in the portal and are seen by mononuclear cell and are acute rejection is with inflammatory and in liver are in on days 3 to with through the for tumor and are that rejection is not associated with a Th1 or cytokine of graft cells is a of liver allograft and it is by specific in for and in but not suggesting that these mediators in the of cell death in the and graft rejection can occur in the absence of CD8 T cell that for the in FasL, and B in liver allograft are NK NK cells on the of their ability to tumor activation or studies that large numbers of host NK cells liver early and express high levels of and Moreover, a NK cell activation was from a liver suggesting that NK cells within the liver have the to mediate of experimental and clinical observations that the liver is than other and that liver can even provide properties for other have to a for mechanisms that for these It is from rat and mouse transplantation of spontaneous liver tolerance that an immune process of some type is in and rat strain since an inflammatory and early liver which can be It has been that the large of the liver and its the early but this is to for the robust that the liver to subsequent Thus, it is to that some process is associated with the mechanisms have been to the liver or the host immune system. These mechanisms can be divided into 3 soluble cellular and features of the liver. 20 it was that the liver and large of soluble class that readily be in the of healthy and liver Thus, it has been that soluble donor class have properties through of and or through of cell death of of the of soluble class on graft have been to In some direct in vivo of rat soluble class allograft class with in other studies soluble class to or allograft or of in The that from that their liver allograft the to a to the suppressive Liver is a from the of recipients of liver can rat allograft but of the mechanism of liver and the of these to be Finally, human can produce a soluble form of Fas that is derived from a the of the and of of the soluble Fas of cells in Moreover, the levels of soluble Fas in graft rejection as compared to with a These data suggest that soluble Fas the in liver In the of of these soluble it has been shown that can function in their in the in vivo is it is that of these is for the tolerogenic properties of liver it is that in with other hepatic to tolerance. these it has been shown that of from liver by the tolerogenic suggesting that some cellular of the graft is can be from studies by In this and of a allograft into a recipient of the same strain as the leads to graft rejection than tolerance. This can be by the fact that the allogeneic donor liver in the recipient in the of the with host a liver. the liver is into the spontaneous tolerance does not occur and the graft is rejected, donor are for of tolerance. This of is in to the of the role of in in which associated with the graft are to be the critical cell type in recipient T cells to donor antigens in secondary lymphoid and destructive This between the liver and other grafts be to multiple not the of which are in the and type of in the various grafts and their for a by the tolerogenic properties of the liver to the ability of cells to migrate of the graft following transplantation, to and to in some with host to a of that can to or of host T for this from the that with have evidence of donor cell in peripheral it has not been to whether donor in clinical allograft recipients is a or an of graft and the of and graft is not of this has not been a of studies have cells with in spontaneous liver tolerance, the of the cell or cells has not been such cell type is the immature DCs found in the liver, as in class and costimulatory are efficient antigen-presenting cells and are of Immature by contrast, not express significant levels of the costimulatory molecules and and as such are of cell and in fact T-cell responses through of immature DCs to to allograft in the absence of although the was Furthermore, DCs from the liver and in to allogeneic T cells in and of the immature DCs to allograft recipients graft APCs in the liver have also been in liver tolerance. LSECs are a unique APCs found in the liver that can present soluble antigen to CD8 T cells but, through this tolerance than Finally, cells, APCs found in the hepatic shown to be for tolerance by the liver. In these of cells with tolerance via the portal mechanisms for the of cells in liver tolerance from recent studies by that cells express that can induce of T cells and that of cells derived from grafts can graft in an acute rejection Finally, unique of the that T cells to in contact with cells, including the LSECs and T-cell or of immune activation and tolerance can be readily demonstrated in the liver. The that to be but to these observations have been cellular rejection in 50% to 75% of liver allograft recipients and the majority of occur within days of transplant The of activated lymphocytes are cells and whereas direct of is is by to and of the of rejection has in the and currently in than 5% of The to and treat acute and rejection are in in a separate CAQ by and colleagues from the The of transplantation tolerance, as the of a allograft in the absence of immunosuppressive represent a major and clinical data have suggested that transplantation tolerance be by and of donor but is of diseases by liver transplantation are to be autoimmune in transplanted is as susceptible to the autoimmune process as the being In particular, evidence for of autoimmune hepatitis is by most whereas data for of primary sclerosing and primary biliary can be from are The to graft rejection is in most cases to significant autoimmune to the but a of graft from Liver transplantation is with to specific of and this as a to the of immunity against cells within the T cells are the primary effector lymphocytes for of immunity against of cells and are of their ability to cells as the of in the of class molecules on the surface of the immune recognition of the hepatitis C allograft be in the containment of of the allograft occur via T cells or via derived from the For the T cells, recognition occur through of molecules, or occur through the of T cells that are by the molecules of the donor liver. Because has on T cells by recipient molecules, is the relative of cells by the donor liver. recent demonstrated the of hepatitis C T cells that are by donor the of the TCR, as well as the to both recipient and allograft in to a of immunity to hepatitis C after liver transplantation.
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Martinez et al. (2005) studied this question.
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