Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

The liver works as a school to educate regulatory immune cells

Abstract

Because of its unique blood supply, the liver maintains a special local immune tolerogenic microenvironment. Moreover, the liver can impart this immune tolerogenic effect on other organs, thus inducing systemic immune tolerance. The network of hepatic regulatory cells is an important mechanism underlying liver tolerance. Many types of liver-resident antigen-presenting cells (APCs) have immune regulatory function, and more importantly, they can also induce the differentiation of circulating immune cells into regulatory cells to further extend systemic tolerance. Thus, the liver can be seen as a type of ‘school’, where liver APCs function as ‘teachers’ and circulating immune cells function as ‘students.’

Introduction

The immune system is the most important weapon used by the body to defend itself against pathogens and unwanted self-cells, but abnormal immune responses sometimes cause severe damage to the host. Therefore, the accuracy of the immune system is often more important than its ability to defend. To accomplish this, the first requirement is for immune cells to distinguish between self and non-self. T cells undergo positive and negative selection in the thymus, where the self-reactive T-cell repertoire dies by apoptosis. This central prevents the immune system from retaining memory to self. However, many low-affinity self-reactive T cells can still escape from the thymus and spread into the periphery.1,2,3 Thus, the second requirement is for the immune response to maintain an appropriate level even when confronted with an enemy, as a weak immune response cannot effectively clear pathogens, but an excessively strong immune response can lead to autoimmune disease and allergy.

The unique systemic circulation within the liver makes it not only able to obtain blood from the hepatic artery, but also through the portal vein, the latter containing nutrients, metabolic products, toxins and soluble antigens.4 Faced with handling all of these components, the liver also plays a role in metabolic detoxification. Moreover, increased evidence demonstrates that the liver is also an important immunotolerant organ. As a striking example of this, liver allografts are accepted when transplanted into hosts with a mismatched major histocompatibility complex (MHC) background in a pig model of transplantation.5 Tolerance is also achieved by intraportal antigen delivery into the liver, which can then induce systemic tolerance.6,7 Similarly, oral tolerance—the systemic tolerance induced by orally administering foreign antigens—is also dependent upon the liver.6 Under pathological states, such as hepatitis viral infection, immune tolerance, rather than an immune response, is often induced in the liver.8

There are several ways to explain why the liver is a site of immune tolerance. The classic hypothesis is that the liver functions as a ‘graveyard’ for T cells. Huang et al.9 found that when T-cell receptor (TCR) transgenic mice were injected with a specific peptide for a given TCR antigen, activated T cells traveled to the liver and died. Later, anti-CD3 administration was also found to induce activated T-cell accumulation and apoptosis in the liver.10 Although this hypothesis drew the attention of many immunologists, it could not explain the observation that effector and memory cells were also generated during viral infection, especially in hepatitis, and could sometimes clear the infection.

Another viable explanation for liver tolerance is its unique hepatic regulatory mechanisms. From an evolutionary and differentiation perspective, the fetal liver has the same hematopoietic function as bone marrow; interestingly, the latter was also found to have immune regulatory potential.11 Many types of liver-resident nonparenchymal cells and hepatocytes can present antigens and often exhibit a unique regulatory function compared with their counterparts in other organs. These antigen-presenting cells (APCs) can also interact with other circulating cells and endow them with regulatory function. In turn, the newly induced regulatory cells can go on to induce regulatory function in other cells, even in the periphery. Thus, resident and circulating cells work cooperatively to form a complex network that maintains liver tolerance. Indeed, an increasing number of studies demonstrate that the liver functions in a dramatic way to control immune responses. In this review, we will discuss how the liver functions as a ‘school’ to educate regulatory cells.

The liver exerts both local and systemic tolerogenic effects

Liver tolerance is not locally restricted to the liver, as crosstalk often occurs between the liver and other organs. This crosstalk regulates the extra-hepatic immune responses that finally lead to systemic tolerance (Figure 1). The most well-known and accepted illustration of this is the systemic immune tolerance induced when a liver is transplanted into a host, where tolerance is induced not only to the liver, but also to skin allografts cotransplanted from the same donor.5 Additionally, liver allografts can survive without immunosuppressive drugs, even though other organs—such as the skin, kidney and heart—are rapidly rejected. Thus, liver allograft protection against donor-specific skin and kidney rejection suggests that allogeneic liver may be able to modulate immune responses in other organs and induce systemic immune tolerance.

Figure 1
figure1

Crosstalk between the liver and other organs can regulate immunity in other organs. Unlike other immune-privileged organs, the liver contains many types of immune cells. (1) The immune response often occurs in the liver during virus infection, transplantation, ectopic antigen expression and so on. (2) The liver can sometimes generate a positive immune response to eliminate various ‘enemies’, (3) which is followed by the generation of immune defense throughout the body. (4) Immune tolerance is more often induced, allowing foreign antigens to persist in the liver. (5) Additionally, the liver can crosstalk with other organs and regulate their immune responses, effectively inducing systemic tolerance. (6) After transferring immune tolerance from the liver to the entire body, systemic immune responses are suppressed, allowing for virus infection, tumor migration, transplant acceptance and so on. CNS, central nervous system; LN, lymph node.

The influenza virus causes respiratory tract infections and induces lung inflammation. Interestingly, influenza can also cause hepatitis even though no viral titers can be detected in the liver, because virus-specific cytotoxic lymphocytes (CTLs) originally generated within the lung can encounter Kupffer cells in the liver and induce hepatocyte apoptosis.12 A similar phenomenon has been observed between the pancreas and the liver, where liver-derived, ex vivo-expanded dendritic cells (DCs) can improve islet allograft survival.13 Taken together, these observations suggest that immune cells traffic between the liver and other organs to regulate local immune responses.

The liver has also been shown to interact with and induce immune tolerance within the central nervous system (CNS). Niemann–Pick disease is characterized by excessive sphingomyelin buildup in the brain, and recovery of acid sphingomyelinase (ASM) expression in the host is key to a cure. While intracranial delivery of an ASM-expressing vector is not viable because ASM-specific antibodies will be produced, Cheng and colleagues14 found that simultaneously delivering an ASM-expressing vector into both the brain and the liver promoted tolerance to this protein and prevented antibody secretion, thus achieving an effective therapy. This suggested that the liver-generated regulatory immune response toward ASM could inhibit the destructive immune response occurring in the brain. Experimental autoimmune encephalomyelitis is a mouse model of the autoimmune disease multiple sclerosis. It is induced in the CNS and can also be controlled by liver tolerance. Liver, but not skin, expression of the disease-associated antigen, myelin basic protein, induces protection from autoimmune neuroinflammation in this model. Intrahepatic MBP expression induces the production of MBP-specific CD4+CD25+Foxp3+ regulatory T cells (Tregs). Adoptively transferring these cells into recipient mice prevents disease,15 further indicating that immune responses generated in the liver can regulate the immune response in the CNS and brain.

Human coagulation factor IX (hF.IX) effectively treats the X-linked bleeding disorder hemophilia B, but immune responses to hF.IX are a concern. Intrahepatic hF.IX expression has been shown to induce Tregs cells that inhibit both T helper (Th) cell subset generation and anti-hF.IX antibody formation.16 Moreover, this tolerance was maintained even after immunizing mice against hF.IX intramuscularly, which normally induces a strong immune response in the absence of intrahepatic hF.IX administration.17 This phenomenon illustrates that the liver can regulate immune responses in muscle or the draining lymph node.

Circulating regulatory immune cell ‘students’ are educated in the liver

Unlike other immune-privileged sites, such as the renal capsule and eye, the liver contains various types and numbers of lymphocytes. Thus, while the liver can potentially eliminate pathogens in situ, immune tolerance usually develops instead. These lymphocytes include both innate (natural killer (NK) and natural killer T (NKT) cells) and adaptive immune cells (T and B cells), which are scattered throughout the parenchyma and migrate through the hepatic sinusoids. Although these cells are capable of immune surveillance and pathogen clearance, most of them acquire or display regulatory function after entering the liver. We therefore call these circulating immune cells ‘students’ that are educated in the liver.

Tregs

Tregs are among the most powerful regulatory cells, playing an important role in restricting immune responses toward self- and foreign antigens. CD25 and Foxp3 expression are two major Treg markers and are essential for their development and function.18,19 While natural Tregs develop in the thymus,20 Tregs in peripheral organs can originate from either proliferated natural Tregs or inducible Tregs, which are induced from Foxp3-negative conventional CD4+ T cells or even differentiated CD4+ T cells.21,22

Normal liver contains relatively few Tregs cells (0.5%–1% of lymphocytes) compared with the spleen, but they play an important role in regulating hepatic immunity. Indeed, decreased Treg frequency or function leads to increasingly dysregulated immune responses in the liver, eventually causing autoimmune disease and primary biliary cirrhosis.23,24,25 Most liver APCs can induce Treg development and recruit circulating Tregs; this will be discussed in detail below. Tregs can functionally suppress other cells in both direct and indirect manners:26 they can directly interact with effector T cells and APCs27 or secrete regulatory cytokines, such as IL-10 and transforming growth factor (TGF)-β.20

Hepatic Tregs play an important role in regulating hepatic immunity and maintaining liver tolerance. Decreased Treg frequency and their impaired function in the liver have been associated with immune-induced liver injury in several cases.23,24,25 Our group previously found that the Tregs frequency increased in a mouse model of ConA-induced injury. Liver injury increased in the mice after Tregs were depleted by removing CD25+ cells; moreover, adoptive transfer of Tregs attenuated ConA-induced liver injury in a TGF-β-dependent manner.28 In an independent study, Tregs cells mediated liver tolerance in a similar ConA-induced mouse model through IL-10 secretion.29 In patients infected with hepatitis C virus, Tregs constitute nearly half of the CD4+ T-cell30 population in the peripheral blood; they are believed to suppress effector T-cell function and induce viral persistence.31,32 Hepatic Tregs also play an important role in liver transplantation. They increase in liver grafts after transplant and are initially required for graft acceptance, as rejection occurs upon anti-CD25 antibody-mediated Treg depletion.33 Interestingly, ectopic antigen expression in the liver induces antigen-specific Tregs, thus supplying a therapeutic strategy to combat autoimmune disease in other organs.15

In contrast to the transplant rejection observed after Treg depletion is performed prior to transplantation, Treg depletion has no effect if performed well after liver transplantation (i.e. 20 days).34 A similar phenomenon occurs in a ConA-induced liver tolerance model, where Tregs rapidly increase in the liver after ConA induction but later return to normal levels.29 These results may explain why steady-state livers have so few Tregs cells: because the liver contains many cells with regulatory function, Tregs may not be needed at steady-state levels or in a tolerance-induced state, but they may be needed to induce tolerance.

NKT cells

NKT cells are a major subset of liver lymphocytes that reside in the sinusoid.35 The liver contains the highest ratio of NKT/conventional T cells compared to other organs.36 NKT cells have features of both T and NK cells. Based on TCR expression, NKT cells can be divided into classical and non-classical NKT cells.35,37 α-GalCer is widely used as the model antigen to investigate NKT cell function, and the non-classical MHC molecule CD1d is believed to present glycolipid antigens to NKT cells.37,38 Many CD1d-expressing hepatic APCs, including Kupffer cells, liver sinusoidal endothelial cells (LSECs), hepatocytes, DCs, B cells and hepatic stellate cells (HSC), can interact with NKT cells.37

Activated NKT cells can express interferon (IFN)-γ and IL-17, which are strong antiviral cytokines. However, they can also secrete large amounts of the anti-inflammatory cytokines IL-4 and IL-10.39,40,41 NKT cells exhibit powerful immune regulation over autoimmune disease.42 The most well-known model is the type 1 diabetes-susceptible non-obese diabetic (NOD) mouse model, where adoptive transfer of NKT cells can prevent diabetes onset,43,44 presumably by IL-4-mediated skewing of CD4+ T cells toward Th2, thus preventing Th1-mediated autoimmune responses in NOD mice.45 Moreover, NKT cells can also suppress immune responses by secreting IL-10 in autoimmune disease.46,47 Interestingly, although IL-17 is often considered to be a pro-inflammatory cytokine, NKT cell-derived IL-17 prevents inflammatory monocyte infiltration in an α-GalCer-induced liver injury model, indicating that it also possesses anti-inflammatory properties.48 Indeed, neutralizing this NKT-derived IL-17 exacerbates hepatitis with increased hepatic neutrophils and monocytes, while pre-injecting IL-17 ameliorates hepatitis and inhibits inflammatory monocyte recruitment to the liver.48

Recently, crosstalk between NKT and other cells within the liver was studied in detail. NKT cells enhance the proliferation and expression of cytotoxic T-lymphocyte antigen (CTLA)-4 on Tregs through IL-2 secretion.49 Oo et al.50 found that α-GalCer-activated NKT cells can indirectly recruit Tregs into the liver, as follows: activated NKT cells first secrete IFN-γ, which then increases IP-10/CXCL10 chemokine expression by Kupffer cells, hepatocytes and biliary epithelial cells. CXCR3-expressing Tregs are then recruited into the liver in a CXCL10-dependent manner and suppress the IL-10-mediated inflammatory response. NKT cells also crosstalk with myeloid-derived suppressor cells (MDSCs), which constitutively express CD1d.51 Immature monocyte recruitment into the liver was found in the acute liver injury model, although suppressive function was not examined.52 Moreover, activated NKT cells crosstalk with DCs in a CD40L–CD40-dependent manner, resulting in semimature DCs that can suppress immune responses.53,54

Natural killer cells

The liver contains much higher NK cell numbers than other organs, comprising 20%–30% of all lymphocytes in the liver.55,56,57 As a major subset of innate immune cells, NK cells play an important role in early pathogen control against viruses and bacteria, as well as in controlling cancer cell growth.58,59 NK cell function is determined by the balance of activating- and inhibitory-receptor expression,60,61 which may be influenced by the liver microenvironment.62,63 The liver contains a prominent NKG2A+Ly49 NK cell subset in a functionally hyporesponsive state, as they exhibit a dampened IFN-γ response to IL-12/IL-18 stimulation. Additionally, adoptively transferred splenic NK cells that migrate into the liver adopt the phenotype and function of liver-resident NK cells.64 Therefore, the local liver microenvironment may modify NK cell receptor expression and responsiveness to cytokine stimulation.

NK cells possess several different regulatory functions, one of which is secreting various cytokines and chemokines.65,66,67 NK cell-derived IL-10 and TGF-β, for example, negatively regulate immune responses and maintain tolerance during transplant and pregnancy.68 NK cells can also inhibit autoreactive T-cell function and proliferation through IL-10 secretion.69 In a transplant model of anti-CD154-induced long-term islet allograft survival in mice, tolerance depends on the MHC class I molecule.70 Further study indicated that while tolerance could be still induced in CD8−/− mice, NK cell depletion by NK1.1 antibody completely abrogated islet allograft persistence after anti-CD154 treatment. Moreover, islet allografts are rejected in perforin-deficient recipients, and perforin-secreting NK cells are sufficient to restore tolerance in these mice.70 Hepatic NK cells also produce chemokines that promote immune tolerance, including macrophage inflammatory protein-1α and -1β, which induce hepatocytes and LSECs to secrete CXCL9 to recruit T cells into the liver, ultimately resulting in T-cell tolerance.71

NK cells also have a unique regulatory function that depends on their cytotoxic ability. Although APCs in skin allografts can home to draining lymph nodes in recipient mice and activate the alloreactive T cells that induce allograft rejection, NK cells can arrest this process by killing APCs and regulating T-cell priming.72 Additionally, NK cells can also detect and lyse autoreactive T cells and DCs.67,73

NK cells cocultured with hepatocytes promote DCs to prime CD4+ T cells, which then acquire Tregs cell properties. This process depends on engaging NKG2A on NK cells,74 as NKG2A signals induce changes in the cytokine milieu of cocultured cells, including decreased TNF-α and increased TGF-β concentrations. In contrast to classical Tregs, NK cell-primed DC-induced Tregs cells exert their suppressive functions through a programmed death-1 (PD-1)-mediated pathway,74 indicating that NK cell receptor signaling can also regulate the immune function of other cells.

Myeloid-derived suppressor cells

MDSCs, which have a high frequency in the liver (approximately 5% of all hepatic cells), include immature monocytes, such as macrophages, granulocytes and DCs, and are identified by the following surface markers: Gr-1+Mac-1+ in mice and CD33+CD11b+CD14 in humans. MDSCs have the powerful ability to suppress T-cell proliferation, inhibit NK cell cytotoxicity,75 and induce the production of regulatory M2 cells76 and Tregs.77 Two distinct MDSC subsets can be distinguished: the monocytic subset (CD11b+Ly6GLY6Chigh) suppresses other cells—particularly by producing inducible nitric oxide synthase and arginase 1—while the granulocytic subset (CD11b+Ly6G+LY6Clow) primarily mediates immunosuppression by producing reactive oxygen species.78,79

MDSCs promote liver immune tolerance through several mechanisms and in various disease models. MDSCs were first found in tumors. In liver carcinoma, MDSCs suppress the anti-tumor activity of T cells and NK cells, thus promoting disease.80 MDSCs from hepatocellular carcinoma patients inhibit autologous NK cell cytotoxicity and cytokine secretion by cell–cell contact, mainly through NKp30 expressed on NK cells.81 Preliminary data demonstrated that NKT cells could recruit MDSCs into the liver to suppress CD4+ T cell-mediated immune responses.82 In a transplant model, cotransplanting HSCs and islet cells leads to the long-term survival of islet allografts. While Treg induction and effector T-cell apoptosis were considered to be the main mechanisms underlying this process, MDSCs have recently been found to also induce immune suppression in this model. Chou et al.83 found that cotransplanting HSCs promoted MDSC generation both in vitro and in vivo and that soluble factors mediated this IFN-γ signaling-dependent process. More importantly, they also found that cotransplanted MDSCs could promote long-term islet allograft survival. MDSCs are also important during viral infection. In a hepatitis B virus (HBV) transgenic mouse model, MDSC frequency in the liver increased from 6.05% in normal mice to 13.6% in transgenic mice. In addition, HBV-transgenic hepatic MDSCs were able to powerfully suppress the generation of hepatitis B surface antigen-specific lymphocytes.84 MDSCs also can work as an important negative feedback regulator for the Th1 immune response within the liver. In a model where TGFβ−/− mice develop acute liver inflammation caused by CD4+ T cell-derived IFN-γ, MDSCs were found adjacent to Th1 cells in the liver. After CD4+ T-cell depletion or the inhibition of IFN-γ signals, MDSCs were significantly reduced.85

In the above examples, MDSCs were located at the sites of ongoing immune response in the liver. More interestingly, however, MDSCs selectively accumulated inside the liver even when the immune response took place elsewhere. In a tumor model using DA-3 cell lines subcutaneously injected into mice, MDSCs homed to and increased in number within the liver. MDSCs were then able to upregulate PD-L1 expression on liver Kupffer cells, contributing to immunosuppression.86

Liver-resident ‘educators’ teach circulating cells in the liver

The liver's unique blood transport system strongly influences its ability to harbor immune regulatory function. Terminal portal vessels function as the main blood supply, and a large number of circulating lymphocytes contained in the blood (approximately 108 per 24 h) encounter liver-resident cells at liver sinusoids. One type of these cells is fenestrated LSECs, which form a layer of thin vessels that function to separate the blood from hepatocytes.87 Kupffer cells and DCs, located in the sinusoidal lumen, are also important liver-resident APCs. The small space of Disse forms another barrier separating LSECs from hepatocytes, and HSCs also reside in these spaces. Because the sinusoids are small in diameter and exhibit low perfusion pressure, leukocytes can easily adhere to this location without expressing selectins. This allows sufficient time for resident APCs, including Kupffer cells, LSECs and DCs, to come into contact with circulating lymphocytes.88 Due to the LSEC fenestrations, circulating lymphocytes can enter into the space of Disse and come into contact with other cells that reside there, such as HSCs and hepatocytes. In addition to functioning to present antigens, APCs first function to recruit lymphocytes from the blood. LSECs and hepatocytes bearing cognate antigens can recruit the corresponding antigen-specific CD8+ T cells in an antigen-dependent manner.89,90 Immune cells can also be recruited to the liver in a chemokine-dependent manner during inflammation.91 For example, expression of CXCR3 on LSECs and CCR4 on DCs is required for Treg recruitment.92 After recruiting circulating lymphocytes, liver-resident APCs will then perform their own immune regulatory functions and, more importantly, induce the differentiation of circulating cells toward a regulatory state. Because of these two features, hepatic APCs are worthy of earning the name ‘teacher’ within the context of the liver (Figure 2, Table 1).

Figure 2
figure2

The regulatory network among the ‘teachers’ and ‘students’ in the liver. The resident hepatic cells (teachers), including hepatocytes, Kupffer cells, DCs, LSECs and HSCs, form a loose blood supply channel called the sinusoid. This unique structure gives the resident cells sufficient room and time to encounter and regulate circulating cells (students), including T cells, NK cells, NKT cells and MDSCs. The crosstalk between the teachers and students forms a complex regulatory network. The effect of the education process on each pair of interacting cells is summarized in Table 1. DC, dendritic cell; HSC, hepatic stellate cell; LSEC, liver sinusoidal endothelial cell; MDSC, myeloid-derived suppressor cell; NK, natural killer cell; NKT, natural killer T cell.

Table 1 The effect of education on regulators

Kupffer cells

Kupffer cells represent 20% of liver nonparenchymal cells and are the largest fixed macrophage population in the body. They reside in the periportal area of the sinusoidal vascular space and are specifically identified by their expression of MHC-II molecules, CD80, CD86 and ICAM-1. Due to their location and slow blood flow, Kupffer cells are perfectly suited to clear endotoxins and microorganisms from the blood. These features additionally facilitate contact between Kupffer cells and other cells, which allows Kupffer cells to ‘educate’ them, thus inducing liver tolerance to many antigen sources.93,94,95

OVA-specific OT-I T cells transferred into mice through the portal vein can detect Kupffer cells loaded with an OVA-derived peptide in the liver, which then induces T-cell tolerance to OVA by causing activation-induced apoptosis.96 The most unique characteristic of Kupffer cells is their ability to secrete the regulatory cytokines IL-10 and TGF-β after LPS stimulation.97 Kupffer cells can also suppress DC-mediated T-cell activation through prostaglandin (PG)E2, 15d-PGJ2 and nitric oxide expression.98,99 Similarly, they can downregulate antigen uptake by LSECs and decrease T-cell activation though TNF-α and IL-10.100 Moreover, they can enhance IL-10 expression by Tregs in the liver, which is very important for maintaining a tolerant microenvironment.101 Studies also indicate that Kupffer cells are important APCs that interact with NKT cells by presenting lipid antigens.102 Thus, Kupffer cells interact in a tolerogenic way with almost all other cell subsets in the liver.

Hepatocytes

Hepatocytes occupy two-thirds of the total cell population in the liver and are responsible for most of its metabolic functions. Facing plenty of gut antigens, as well as neoantigens synthesized during the metabolic process, hepatocytes can act like APCs and function to induce tolerance. Although they are located beyond the sinusoid, hepatocytes can contact T cells via their microvilli that extend through the endothelium.103 Although MHC and CD1 expression on the surface of hepatocytes allows them to present antigens to both T and NKT cells, their lack of costimulatory molecules and CD40 expression skews this process toward tolerance rather than activation by several different mechanisms. After encountering these tolerance-inducing hepatocytes, T cells are clonally eliminated by apoptosis.104,105 Moreover, Th2 cells are preferentially induced when naïve CD4+ T cells encounter hepatocytes, dampening the Th1 type response and, consequently, CTL-mediated antiviral immunity.106 This impaired Th1 cell induction may be caused by low levels of Delta-like Notch ligand, a key promoter of the Th1 response, in hepatocytes.107 Hepatocytes also induce antigen-specific Tregs cells, which prevent autoimmune disease.15 Furthermore, NK cell–hepatocyte interaction via NKG2A-Qa-1b engagement can result in increased IL-10 and decreased IFN-γ production by NK cells.74 When encountering type I IFN-secreting NKT cells, hepatocytes can induce IL-10-expressing CD8+ T cells, which also exhibit regulatory function.108

LSECs

LSECs form the structural base of hepatic sinusoids. Because hepatic sinusoid structures do not contain an organized basement membrane layer, LSECs are the first APCs to contact antigens. As scavenger cells, LSECs exhibit a powerful antigen uptake ability that is even stronger than that of Kupffer cells,109 and they can process and present antigens to other cells. However, their lack of MHC molecule expression and IL-12 secretion prevents them from functioning like professional APCs, and thus, they cannot stimulate Th cells to clonally expand or be eliminated.110 LSECs also play an important role in inducing oral, as well as LSEC-primed CD8+ T cell tolerance, which is mostly dependent on the expression of B7-H1 on LSECs and PD-1 on CD8+ T cells.111,112

Unlike other APCs in the liver, LSECs possess regulatory functions independent of antigen presentation. They express various C-type lectins, such as LSECtin, which inhibit T-cell proliferation and effector-cytokine secretion and induce T-cell apoptosis by interacting with CD44 on activated T cells.113,114 Interestingly, while LSECs can induce Treg differentiation to suppress Th cell-mediated immune responses, they can also induce CD25lowFoxp3 regulatory T cells.115 LSECs can also directly downregulate the ability of DCs to activate T cells.116

Hepatic stellate cells

HSCs are located in the subendothelial space of Disse, and their main metabolic function is storing vitamin A and fat.117 HSCs can express many cytokines, participate in antimicrobial immunity, and function as APCs to cross-prime CD8+ T cells and present lipid antigens to NKT cells.118 Additionally, activated HSCs induce B7-H1- and TNF-related apoptosis-inducing ligand-mediated T-cell apoptosis.119,120 HSCs also induce CD4+CD25+Foxp3+ Tregs cell expansion from CD4+CD25+Foxp3 effector T cells in an IL-2-dependent manner; these Tregs efficiently inhibit anti-CD3-induced T-cell proliferation.121 Further study of the islet and HSC cotransfer mouse model (described above) showed that HSCs play dual roles in this process: they induce donor-derived antigen-specific effector T-cell apoptosis and expand Tregs.122 Moreover, HSCs from IFN-γ-receptor 1 knockout mice lose this ability to protect, demonstrating that HSC-derived IFN-γ signaling is very important for inducing Tregs.122

Dendritic cells

The liver contains more DCs than any other parenchymal organ.123 Liver DCs include three subsets: myeloid and lymphoid DCs located around the periportal areas and plasmacytoid DCs (pDCs) residing in the liver parenchyma.124 Although DCs are often considered to be professional APCs, hepatic DCs exhibit an immature phenotype with tolerogenic properties.13,125,126 IL-10highIL-12low regulatory DCs can be induced by MCSF and hepatocyte growth factor secreted by stromal cells,127,128 which can regulate Th2, but not Th1, responses.129 Liver pDCs (CD11clowb220+LY6C+CD11bSiglecH+) are very weak T-cell stimulators, as they lack CD40, CD80 and CD86 expression.130 Resting liver DCs express PD-1 and CTLA-4 inhibitory molecules that induce circulating CD8+ T-cell tolerance.131 Liver mDCs (CD11c+CD8αCD11b+) exhibit ‘endotoxin tolerance’, because they are resistant to LPS stimulation.132 This unique phenomenon is important for maintaining tolerance within the liver microenvironment. When transferred into allogeneic recipients, liver mDCs can elicit IL-10-producing T cells, which helps to induce tolerance to pancreatic islet allografts.13,133 Furthermore, liver DCs can induce CD4+CD25+ regulatory T cells after interacting with NK cells and hepatocytes.74

pDCs have been shown to mediate oral tolerance by suppressing antigen-specific CD4+ and CD8+ T-cell function in the liver.134 Additionally, liver pDCs preferentially induce Th2 responses and promote CD4+ T-cell apoptosis. CpG-stimulated human pDCs mediate Treg induction, and direct contact between pDCs and CD4+ T cells is necessary to induce Tregs cells.135 Further study indicated that human liver DCs generated more Tregs cells in an IL-10-dependent manner than blood DCs.126 Interestingly, the impaired T-cell proliferation induced by liver pDCs can be rescued by blocking Treg-derived IL-10.136

Future directions

As described in detail above, the liver is a unique organ with tolerogenic properties that could be used to suppress unwanted immune responses. When antigen is presented to T cells by APCs residing in liver sinusoids, including LSECs, Kupffer cells and DCs, the immune response can be skewed toward tolerance. Thus, systemic tolerance induced by this method may be very suitable for treating autoimmune diseases caused by known antigens. One encouraging study showed that inducing liver regulatory DCs by administering Toll-like receptor agonists could lead to the remission of autoimmune disease.137 These liver tolerogenic mechanisms may also be useful in preventing transplant rejection.138,139 Thus, tolerization by liver APCs may be an effective approach to prevent antigen-specific allograft rejection and cure autoimmune disease.

As the liver can interact with other organs to induce systemic tolerance, curing extra-hepatic immune disease by manipulating liver immunity may be possible.14,17,140 The experimental autoimmune encephalomyelitis animal model for multiple sclerosis described above is a good example of this, where Luth et al.15 ingeniously expressed MBP in the liver either by transient gene transfer or in stable liver-specific MBP-transgenic mice. This ectopic MBP expression induced MBP-specific CD4+CD25+Foxp3+ Tregs cells in the liver, which were then exported to the central nervous system to suppress the MBP-specific CD4+ T cells residing there, finally protecting the mice from autoimmune disease. A similar therapeutic strategy may be beneficial for other organs in which autoimmune disease occurs, such as the heart, joints and skin.

To optimize liver-induced systemic tolerance, efficiently and accurately delivering the target gene to tolerogenic APCs (particularly hepatocytes) is very important. One method of achieving this is to use an improved background vector and promoter with minimal innate immune activation; this strategy is discussed in depth by LoDuca et al.140 Another solution is to combine a chemokine with nanoparticles to transfer the gene or gene-expressing cells into the liver through the sinusoids to interact with tolerogenic APCs. In fact, nanocapsules have already been used to deliver a therapeutic gene into LSECs, and its expression cured hemophilia A in mice.141

The tolerogenic property of the liver is a double-edged sword. On one side, it can be used to create tolerance to an unwanted immune response. On the other, tolerance may also cause harm, such as in hepatitis virus infection and cancer. Because viral and cancer antigens are continuously expressed in the liver, the immune response may be unresponsive and unable to control these diseases. Therefore, restricting and clearing antigens in the liver may be an effective solution to reverse immune tolerance. Recently, we found that an siRNA called 3p-HBx-siRNA strongly inhibited HBV replication, which was accompanied by an enhanced innate immune response against HBV.142 Downstream of tolerance formation, breaking liver tolerance will also be required to overcome the regulatory functions of liver immune cells. This may be a difficult task for researchers to face, as the immune regulatory cells in the liver form a complex and stable network to maintain liver tolerance, as described above. Therefore, the remaining key questions to answer in the future are as follows: Which immune cell subset has the most control over immune tolerance, and can specific depletion of these cells reverse tolerance? In fact, breaking liver tolerance has been successful only in a few rare cases. Moving forward, the mechanisms underlying tolerance require further understanding, and effective techniques to study these mechanisms need to be improved.

References

  1. 1

    Gallegos AM, Bevan MJ . Central tolerance: good but imperfect. Immunol Rev 2006; 209: 290–296.

    Article  Google Scholar 

  2. 2

    Palmer E . Negative selection–learing out the bad apples from the T-cell repertoire. Nat Rev Immunol 2003; 3: 383–391.

    CAS  Article  PubMed  Google Scholar 

  3. 3

    Bouneaud C, Kourilsky P, Bousso P . Impact of negative selection on the T cell repertoire reactive to a self-peptide: a large fraction of T cell clones escapes clonal deletion. Immunity 2000; 13: 829–840.

    CAS  Article  PubMed  Google Scholar 

  4. 4

    Bertolino P, McCaughan GW, Bowen DG . Role of primary intrahepatic T-cell activation in the ‘liver tolerance effect’. Immunol Cell Biol 2002; 80: 84–92.

    Article  PubMed  Google Scholar 

  5. 5

    Calne RY, Sells RA, Pena JR, Davis DR, Millard PR, Herbertson BM et al. Induction of immunological tolerance by porcine liver allografts. Nature 1969; 223: 472–476.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  6. 6

    Cantor HM, Dumont AE . Hepatic suppression of sensitization to antigen absorbed into the portal system. Nature 1967; 215: 744–745.

    CAS  Article  PubMed  Google Scholar 

  7. 7

    Triger DR, Cynamon MH, Wright R . Studies on hepatic uptake of antigen. I. Comparison of inferior vena cava and portal vein routes of immunization. Immunology 1973; 25: 941–950.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. 8

    Protzer U, Maini MK, Knolle PA . Living in the liver: hepatic infections. Nat Rev Immunol 2012; 12: 201–213.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  9. 9

    Huang L, Soldevila G, Leeker M, Flavell R, Crispe IN . The liver eliminates T cells undergoing antigen-triggered apoptosis in vivo. Immunity 1994; 1: 741–749.

    CAS  Article  PubMed  Google Scholar 

  10. 10

    Mehal WZ, Juedes AE, Crispe IN . Selective retention of activated CD8+ T cells by the normal liver. J Immunol 1999; 163: 3202–3210.

    CAS  PubMed  Google Scholar 

  11. 11

    Zhao E, Xu H, Wang L, Kryczek I, Wu K, Hu Y et al. Bone marrow and the control of immunity. Cell Mol Immunol 2012; 9: 11–19.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  12. 12

    Polakos NK, Cornejo JC, Murray DA, Wright KO, Treanor JJ, Crispe IN et al. Kupffer cell-dependent hepatitis occurs during influenza infection. Am J Pathol 2006; 168: 1169–1178; quiz 1404–1165.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  13. 13

    Rastellini C, Lu L, Ricordi C, Starzl TE, Rao AS, Thomson AW . Granulocyte/macrophage colony-stimulating factor-stimulated hepatic dendritic cell progenitors prolong pancreatic islet allograft survival. Transplantation 1995; 60: 1366–1370.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14

    Passini MA, Bu J, Fidler JA, Ziegler RJ, Foley JW, Dodge JC et al. Combination brain and systemic injections of AAV provide maximal functional and survival benefits in the Niemann–Pick mouse. Proc Natl Acad Sci U S A 2007; 104: 9505–9510.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  15. 15

    Luth S, Huber S, Schramm C, Buch T, Zander S, Stadelmann C et al. Ectopic expression of neural autoantigen in mouse liver suppresses experimental autoimmune neuroinflammation by inducing antigen-specific Tregs. J Clin Invest 2008; 118: 3403–3410.

    PubMed  PubMed Central  Google Scholar 

  16. 16

    Mingozzi F, Liu YL, Dobrzynski E, Kaufhold A, Liu JH, Wang Y et al. Induction of immune tolerance to coagulation factor IX antigen by in vivo hepatic gene transfer. J Clin Invest 2003; 111: 1347–1356.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  17. 17

    Hoffman BE, Dobrzynski E, Wang L, Hirao L, Mingozzi F, Cao O et al. Muscle as a target for supplementary factor IX gene transfer. Human Gene Ther 2007; 18: 603–613.

    CAS  Article  Google Scholar 

  18. 18

    Sakaguchi S . Naturally arising Foxp3-expressing CD25+CD4+ regulatory T cells in immunological tolerance to self and non-self. Nat Immunol 2005; 6: 345–352.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  19. 19

    Sakaguchi S, Miyara M, Costantino CM, Hafler DA . FOXP3+ regulatory T cells in the human immune system. Nat Rev Immunol 2010; 10: 490–500.

    CAS  Article  PubMed  Google Scholar 

  20. 20

    Sakaguchi S, Yamaguchi T, Nomura T, Ono M . Regulatory T cells and immune tolerance. Cell 2008; 133: 775–787.

    CAS  Article  Google Scholar 

  21. 21

    Walker LS, Chodos A, Eggena M, Dooms H, Abbas AK . Antigen-dependent proliferation of CD4+ CD25+ regulatory T cells in vivo. J Exp Med 2003; 198: 249–258.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  22. 22

    Liang S, Alard P, Zhao Y, Parnell S, Clark SL, Kosiewicz M . M. Conversion of CD4+ CD25 cells into CD4+ CD25+ regulatory T cells in vivo requires B7 costimulation, but not the thymus. J Exp Med 2005; 201: 127–137.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  23. 23

    Longhi MS, Ma Y, Bogdanos DP, Cheeseman P, Mieli-Vergani G, Vergani D . Impairment of CD4+CD25+ regulatory T-cells in autoimmune liver disease. J Hepatol 2004; 41: 31–37.

    CAS  Article  PubMed  Google Scholar 

  24. 24

    Lan RY, Cheng C, Lian ZX, Tsuneyama K, Yang GX, Moritoki Y et al. Liver-targeted and peripheral blood alterations of regulatory T cells in primary biliary cirrhosis. Hepatology 2006; 43: 729–737.

    Article  PubMed  Google Scholar 

  25. 25

    Longhi MS, Hussain MJ, Mitry RR, Arora SK, Mieli-Vergani G, Vergani D et al. Functional study of CD4+CD25+ regulatory T cells in health and autoimmune hepatitis. J Immunol 2006; 176: 4484–4491.

    CAS  Article  PubMed  Google Scholar 

  26. 26

    O'Garra A, Vieira P . Regulatory T cells and mechanisms of immune system control. Nat Med 2004; 10: 801–805.

    CAS  Article  PubMed  Google Scholar 

  27. 27

    Bopp T, Becker C, Klein M, Klein-Hessling S, Palmetshofer A, Serfling E et al. Cyclic adenosine monophosphate is a key component of regulatory T cell-mediated suppression. J Exp Med 2007; 204: 1303–1310.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  28. 28

    Wei HX, Chuang YH, Li B, Wei H, Sun R, Moritoki Y et al. CD4+ CD25+ Foxp3+ regulatory T cells protect against T cell-mediated fulminant hepatitis in a TGF-beta-dependent manner in mice. J Immunol 2008; 181: 7221–7229.

    CAS  Article  PubMed  Google Scholar 

  29. 29

    Erhardt A, Biburger M, Papadopoulos T, Tiegs G . IL-10, regulatory T cells, and Kupffer cells mediate tolerance in concanavalin A-induced liver injury in mice. Hepatology 2007; 45: 475–485.

    CAS  Article  Google Scholar 

  30. 30

    Ward SM, Fox BC, Brown PJ, Worthington J, Fox SB, Chapman RW et al. Quantification and localisation of FOXP3+ T lymphocytes and relation to hepatic inflammation during chronic HCV infection. J Hepatol 2007; 47: 316–324.

    CAS  Article  PubMed  Google Scholar 

  31. 31

    Rushbrook SM, Ward SM, Unitt E, Vowler SL, Lucas M, Klenerman P et al. Regulatory T cells suppress in vitro proliferation of virus-specific CD8+ T cells during persistent hepatitis C virus infection. J Virol 2005; 79: 7852–7859.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  32. 32

    Boettler T, Spangenberg HC, Neumann-Haefelin C, Panther E, Urbani S, Ferrari C et al. T cells with a CD4+CD25+ regulatory phenotype suppress in vitro proliferation of virus-specific CD8+ T cells during chronic hepatitis C virus infection. J Virol 2005; 79: 7860–7867.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  33. 33

    Li W, Kuhr CS, Zheng XX, Carper K, Thomson AW, Reyes JD et al. New insights into mechanisms of spontaneous liver transplant tolerance: the role of Foxp3-expressing CD25+CD4+ regulatory T cells. Am J Transplant 2008; 8: 1639–1651.

    CAS  Article  PubMed  Google Scholar 

  34. 34

    Jiang X, Morita M, Sugioka A, Harada M, Kojo S, Wakao H et al. The importance of CD25+ CD4+ regulatory T cells in mouse hepatic allograft tolerance. Liver Transplant 2006; 12: 1112–1118.

    Article  Google Scholar 

  35. 35

    Emoto M, Kaufmann SH . Liver NKT cells: an account of heterogeneity. Trends Immunol 2003; 24: 364–369.

    CAS  Article  PubMed  Google Scholar 

  36. 36

    Eberl G, Lees R, Smiley ST, Taniguchi M, Grusby MJ, MacDonald H . R. Tissue-specific segregation of CD1d-dependent and CD1d-independent NK T cells. J Immunol 1999; 162: 6410–6419.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. 37

    Bendelac A, Savage PB, Teyton L . The biology of NKT cells. Ann Rev Immunol 2007; 25: 297–336.

    CAS  Article  Google Scholar 

  38. 38

    Kawano T, Cui J, Koezuka Y, Toura I, Kaneko Y, Motoki K et al. CD1d-restricted and TCR-mediated activation of valpha14 NKT cells by glycosylceramides. Science 1997; 278: 1626–1629.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  39. 39

    Taniguchi M, Harada M, Kojo S, Nakayama T, Wakao H . The regulatory role of Valpha14 NKT cells in innate and acquired immune response. Ann Rev Immunol 2003; 21: 483–513.

    CAS  Article  Google Scholar 

  40. 40

    van Kaer L . NKT cells: T lymphocytes with innate effector functions. Curr Opin Immunol 2007; 19: 354–364.

    CAS  Article  PubMed  Google Scholar 

  41. 41

    Kronenberg M . Toward an understanding of NKT cell biology: progress and paradoxes. Ann Rev Immunol 2005; 23: 877–900.

    CAS  Article  Google Scholar 

  42. 42

    Linsen L, Somers V, Stinissen P . Immunoregulation of autoimmunity by natural killer T cells. Hum Immunol 2005; 66: 1193–1202.

    CAS  Article  PubMed  Google Scholar 

  43. 43

    Novak J, Lehuen A . Mechanism of regulation of autoimmunity by iNKT cells. Cytokine 2011; 53: 263–270.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  44. 44

    Lehuen A, Diana J, Zaccone P, Cooke A . Immune cell crosstalk in type 1 diabetes. Nat Rev Immunol 2010; 10: 501–513.

    CAS  Article  PubMed  Google Scholar 

  45. 45

    Hammond KJ, Kronenberg M . Natural killer T cells: natural or unnatural regulators of autoimmunity? Curr Opin Immunol 2003; 15: 683–689.

    CAS  Article  PubMed  Google Scholar 

  46. 46

    van Kaer L . Natural killer T cells as targets for immunotherapy of autoimmune diseases. Immunol Cell Biol 2004; 82: 315–322.

    CAS  Article  PubMed  Google Scholar 

  47. 47

    Yamamura T, Sakuishi K, Illes Z, Miyake S . Understanding the behavior of invariant NKT cells in autoimmune diseases. J Neuroimmunol 2007; 191: 8–15.

    CAS  Article  PubMed  Google Scholar 

  48. 48

    Wondimu Z, Santodomingo-Garzon T, Le T, Swain MG . Protective role of interleukin-17 in murine NKT cell-driven acute experimental hepatitis. Am J Pathol 2010; 177: 2334–2346.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  49. 49

    La Cava A, van Kaer L, Fu Dong S . CD4+CD25+ Tregs and NKT cells: regulators regulating regulators. Trends Immunol 2006; 27: 322–327.

    CAS  Article  PubMed  Google Scholar 

  50. 50

    Santodomingo-Garzon T, Han J, Le T, Yang Y, Swain MG . Natural killer T cells regulate the homing of chemokine CXC receptor 3-positive regulatory T cells to the liver in mice. Hepatology 2009; 49: 1267–1276.

    CAS  Article  PubMed  Google Scholar 

  51. 51

    Hegde S, Fox L, Wang X, Gumperz JE . Autoreactive natural killer T cells: promoting immune protection and immune tolerance through varied interactions with myeloid antigen-presenting cells. Immunology 2010; 130: 471–483.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  52. 52

    Karlmark KR, Weiskirchen R, Zimmermann HW, Gassler N, Ginhoux F, Weber C et al. Hepatic recruitment of the inflammatory Gr1+ monocyte subset upon liver injury promotes hepatic fibrosis. Hepatology 2009; 50: 261–274.

    CAS  PubMed  Google Scholar 

  53. 53

    Kitamura H, Iwakabe K, Yahata T, Nishimura S, Ohta A, Ohmi Y et al. The natural killer T (NKT) cell ligand alpha-galactosylceramide demonstrates its immunopotentiating effect by inducing interleukin (IL)-12 production by dendritic cells and IL-12 receptor expression on NKT cells. J Exp Med 1999; 189: 1121–1128.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  54. 54

    Nowak M, Stein-Streilein J . Invariant NKT cells and tolerance. Int Rev Immunol 2007; 26: 95–119.

    CAS  Article  PubMed  Google Scholar 

  55. 55

    Racanelli V, Rehermann B . The liver as an immunological organ. Hepatology 2006; 43: S54–62.

    CAS  Article  Google Scholar 

  56. 56

    Crispe IN . The liver as a lymphoid organ. Ann Rev Immunol 2009; 27: 147–163.

    CAS  Article  Google Scholar 

  57. 57

    Gao B, Jeong WI, Tian Z . Liver: an organ with predominant innate immunity. Hepatology 2008; 47: 729–736.

    CAS  Article  Google Scholar 

  58. 58

    Trinchieri G . Biology of natural killer cells. Adv Immunol 1989; 47: 187–376.

    CAS  Article  Google Scholar 

  59. 59

    Vivier E, Tomasello E, Baratin M, Walzer T, Ugolini S . Functions of natural killer cells. Nat Immunol 2008; 9: 503–510.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  60. 60

    McQueen KL, Parham P . Variable receptors controlling activation and inhibition of NK cells. Curr Opin Immunol 2002; 14: 615–621.

    CAS  Article  PubMed  Google Scholar 

  61. 61

    Lanier LL . NK cell recognition. Ann Rev Immunol 2005; 23: 225–274.

    CAS  Article  Google Scholar 

  62. 62

    Wu L, Zhang C, Zhang J . HMBOX1 negatively regulates NK cell functions by suppressing the NKG2D/DAP10 signaling pathway. Cell Mol Immunol 2011; 8: 433–440.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  63. 63

    Jiang X, Chen Y, Peng H, Tian Z . Single line or parallel lines: NK cell differentiation driven by T-bet and Eomes. Cell Mol Immunol 2012; 9: 193–194.

    Article  PubMed  PubMed Central  Google Scholar 

  64. 64

    Lassen MG, Lukens JR, Dolina JS, Brown MG, Hahn YS . Intrahepatic IL-10 maintains NKG2A+Ly49- liver NK cells in a functionally hyporesponsive state. J Immunol 2010; 184: 2693–2701.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  65. 65

    Raulet DH . Interplay of natural killer cells and their receptors with the adaptive immune response. Nat Immunol 2004; 5: 996–1002.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  66. 66

    Moretta A, Marcenaro E, Parolini S, Ferlazzo G, Moretta L . NK cells at the interface between innate and adaptive immunity. Cell death and differentiation 2008; 15: 226–233.

    CAS  Article  PubMed  Google Scholar 

  67. 67

    Zhang C, Zhang J, Tian Z . The regulatory effect of natural killer cells: do ‘NK-reg cells’ exist? Cell Mol Immunol 2006; 3: 241–254.

    CAS  PubMed  Google Scholar 

  68. 68

    Saito S, Nakashima A, Myojo-Higuma S, Shiozaki A . The balance between cytotoxic NK cells and regulatory NK cells in human pregnancy. J Reprod Immunol 2008; 77: 14–22.

    Article  CAS  PubMed  Google Scholar 

  69. 69

    Deniz G, Erten G, Kucuksezer UC, Kocacik D, Karagiannidis C, Aktas E et al. Regulatory NK cells suppress antigen-specific T cell responses. J Immunol 2008; 180: 850–857.

    CAS  Article  PubMed  Google Scholar 

  70. 70

    Beilke JN, Kuhl NR, van Kaer L, Gill RG . NK cells promote islet allograft tolerance via a perforin-dependent mechanism. Nat Med 2005; 11: 1059–1065.

    CAS  Article  PubMed  Google Scholar 

  71. 71

    Crispe IN . Hepatic T cells and liver tolerance. Nat Rev Immunol 2003; 3: 51–62.

    CAS  Article  Google Scholar 

  72. 72

    Yu G, Xu X, Vu MD, Kilpatrick ED, Li XC . NK cells promote transplant tolerance by killing donor antigen-presenting cells. J Exp Med 2006; 203: 1851–1858.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  73. 73

    Cooper MA, Fehniger TA, Fuchs A, Colonna M, Caligiuri MA . NK cell and DC interactions. Trends Immunol 2004; 25: 47–52.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  74. 74

    Jinushi M, Takehara T, Tatsumi T, Yamaguchi S, Sakamori R, Hiramatsu N et al. Natural killer cell and hepatic cell interaction via NKG2A leads to dendritic cell-mediated induction of CD4 CD25 T cells with PD-1-dependent regulatory activities. Immunology 2007; 120: 73–82.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  75. 75

    Liu C, Yu S, Kappes J, Wang J, Grizzle WE, Zinn KR et al. Expansion of spleen myeloid suppressor cells represses NK cell cytotoxicity in tumor-bearing host. Blood 2007; 109: 4336–4342.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  76. 76

    Sinha P, Clements VK, Bunt SK, Albelda SM, Ostrand-Rosenberg S . Cross-talk between myeloid-derived suppressor cells and macrophages subverts tumor immunity toward a type 2 response. J Immunol 2007; 179: 977–983.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  77. 77

    Huang B, Pan PY, Li Q, Sato AI, Levy DE, Bromberg J et al. Gr-1+CD115+ immature myeloid suppressor cells mediate the development of tumor-induced T regulatory cells and T-cell anergy in tumor-bearing host. Cancer Res 2006; 66: 1123–1131.

    CAS  Article  PubMed  Google Scholar 

  78. 78

    Gabrilovich DI, Nagaraj S . Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol 2009; 9: 162–174.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  79. 79

    Nagaraj S, Schrum AG, Cho HI, Celis E, Gabrilovich DI . Mechanism of T cell tolerance induced by myeloid-derived suppressor cells. J Immunol 2010; 184: 3106–3116.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  80. 80

    Greten TF, Manns MP, Korangy F . Myeloid derived suppressor cells in human diseases. Int Immunopharm 2011; 11: 802–807.

    CAS  Article  Google Scholar 

  81. 81

    Hoechst B, Voigtlaender T, Ormandy L, Gamrekelashvili J, Zhao F, Wedemeyer H et al. Myeloid derived suppressor cells inhibit natural killer cells in patients with hepatocellular carcinoma via the NKp30 receptor. Hepatology 2009; 50: 799–807.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  82. 82

    Santodomingo-Garzon T, Swain MG . Role of NKT cells in autoimmune liver disease. Autoimmun Rev 2011; 10: 793–800.

    CAS  Article  PubMed  Google Scholar 

  83. 83

    Chou HS, Hsieh CC, Yang HR, Wang L, Arakawa Y, Brown K et al. Hepatic stellate cells regulate immune response by way of induction of myeloid suppressor cells in mice. Hepatology 2011; 53: 1007–1019.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  84. 84

    Chen S, Akbar SM, Abe M, Hiasa Y, Onji M . Immunosuppressive functions of hepatic myeloid-derived suppressor cells of normal mice and in a murine model of chronic hepatitis B virus. Clin Exp Immunol 2011; 166: 134–142.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  85. 85

    Cripps JG, Wang J, Maria A, Blumenthal I, Gorham JD . Type 1 T helper cells induce the accumulation of myeloid-derived suppressor cells in the inflamed Tgfb1 knockout mouse liver. Hepatology 2010; 52: 1350–1359.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  86. 86

    Ilkovitch D, Lopez DM . The liver is a site for tumor-induced myeloid-derived suppressor cell accumulation and immunosuppression. Cancer Res 2009; 69: 5514–5521.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  87. 87

    Wick MJ, Leithauser F, Reimann J . The hepatic immune system. Crit Rev Immunol 2002; 22: 47–103.

    CAS  Article  PubMed  Google Scholar 

  88. 88

    Wong J, Johnston B, Lee SS, Bullard DC, Smith CW, Beaudet AL et al. A minimal role for selectins in the recruitment of leukocytes into the inflamed liver microvasculature. J Clin Invest 1997; 99: 2782–2790.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  89. 89

    Bertolino P, Bowen DG, McCaughan GW, Fazekas de St Groth B . Antigen-specific primary activation of CD8+ T cells within the liver. J Immunol 2001; 166: 5430–5438.

    CAS  Article  PubMed  Google Scholar 

  90. 90

    von Oppen N, Schurich A, Hegenbarth S, Stabenow D, Tolba R, Weiskirchen R et al. Systemic antigen cross-presented by liver sinusoidal endothelial cells induces liver-specific CD8 T-cell retention and tolerization. Hepatology 2009; 49: 1664–1672.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  91. 91

    Oo YH, Adams DH . The role of chemokines in the recruitment of lymphocytes to the liver. J Autoimmun 2010; 34: 45–54.

    CAS  Article  PubMed  Google Scholar 

  92. 92

    Oo YH, Weston CJ, Lalor PF, Curbishley SM, Withers DR, Reynolds GM et al. Distinct roles for CCR4 and CXCR3 in the recruitment and positioning of regulatory T cells in the inflamed human liver. J Immunol 2010; 184: 2886–2898.

    CAS  Article  PubMed  Google Scholar 

  93. 93

    Ju C, McCoy JP, Chung CJ, Graf ML, Pohl LR . Tolerogenic role of Kupffer cells in allergic reactions. Chem Res Toxicol 2003; 16: 1514–1519.

    CAS  Article  PubMed  Google Scholar 

  94. 94

    Callery MP, Kamei T, Flye MW . Kupffer cell blockade inhibits induction of tolerance by the portal venous route. Transplantation 1989; 47: 1092–1094.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  95. 95

    Sato K, Yabuki K, Haba T, Maekawa T . Role of Kupffer cells in the induction of tolerance after liver transplantation. J Surg Res 1996; 63: 433–438.

    CAS  Article  PubMed  Google Scholar 

  96. 96

    Kuniyasu Y, Marfani SM, Inayat IB, Sheikh SZ, Mehal WZ . Kupffer cells required for high affinity peptide-induced deletion, not retention, of activated CD8+ T cells by mouse liver. Hepatology 2004; 39: 1017–1027.

    Article  PubMed  PubMed Central  Google Scholar 

  97. 97

    Knolle P, Schlaak J, Uhrig A, Kempf P, Meyer zum Buschenfelde KH, Gerken G . Human Kupffer cells secrete IL-10 in response to lipopolysaccharide (LPS) challenge. J Hepatol 1995; 22: 226–229.

    CAS  Article  PubMed  Google Scholar 

  98. 98

    You Q, Cheng L, Kedl RM, Ju C . Mechanism of T cell tolerance induction by murine hepatic Kupffer cells. Hepatology 2008; 48: 978–990.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  99. 99

    Roland CR, Walp L, Stack RM, Flye MW . Outcome of Kupffer cell antigen presentation to a cloned murine Th1 lymphocyte depends on the inducibility of nitric oxide synthase by IFN-gamma. J Immunol 1994; 153: 5453–5464.

    CAS  PubMed  Google Scholar 

  100. 100

    Carambia A, Herkel J . CD4 T cells in hepatic immune tolerance. J Autoimmun 2010; 34: 23–28.

    CAS  Article  PubMed  Google Scholar 

  101. 101

    Breous E, Somanathan S, Vandenberghe LH, Wilson JM . Hepatic regulatory T cells and Kupffer cells are crucial mediators of systemic T cell tolerance to antigens targeting murine liver. Hepatology 2009; 50: 612–621.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  102. 102

    Schmieg J, Yang G, Franck RW, van Rooijen N, Tsuji M . Glycolipid presentation to natural killer T cells differs in an organ-dependent fashion. Proc Natl Acad Sci U S A 2005; 102: 1127–1132.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  103. 103

    Warren A, Le Couteur DG, Fraser R, Bowen DG, McCaughan GW, Bertolino P . T lymphocytes interact with hepatocytes through fenestrations in murine liver sinusoidal endothelial cells. Hepatology 2006; 44: 1182–1190.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  104. 104

    Bertolino P, Trescol-Biemont MC, Rabourdin-Combe C . Hepatocytes induce functional activation of naive CD8+ T lymphocytes but fail to promote survival. Eur J Immunol 1998; 28: 221–236.

    CAS  Article  PubMed  Google Scholar 

  105. 105

    Holz LE, Benseler V, Bowen DG, Bouillet P, Strasser A, O'Reilly L et al. Intrahepatic murine CD8 T-cell activation associates with a distinct phenotype leading to Bim-dependent death. Gastroenterology 2008; 135: 989–997.

    Article  PubMed  PubMed Central  Google Scholar 

  106. 106

    Wiegard C, Wolint P, Frenzel C, Cheruti U, Schmitt E, Oxenius A et al. Defective T helper response of hepatocyte-stimulated CD4 T cells impairs antiviral CD8 response and viral clearance. Gastroenterology 2007; 133: 2010–2018.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  107. 107

    Amsen D, Blander JM, Lee GR, Tanigaki K, Honjo T, Flavell RA . Instruction of distinct CD4 T helper cell fates by different notch ligands on antigen-presenting cells. Cell 2004; 117: 515–526.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  108. 108

    Wahl C, Bochtler P, Schirmbeck R, Reimann J . Type I IFN-producing CD4 Valpha14i NKT cells facilitate priming of IL-10-producing CD8 T cells by hepatocytes. J Immunol 2007; 178: 2083–2093.

    CAS  Article  PubMed  Google Scholar 

  109. 109

    Knolle PA, Gerken G . Local control of the immune response in the liver. Immunol Rev 2000; 174: 21–34.

    CAS  Article  PubMed  Google Scholar 

  110. 110

    Knolle PA, Schmitt E, Jin S, Germann T, Duchmann R, Hegenbarth S et al. Induction of cytokine production in naive CD4+ T cells by antigen-presenting murine liver sinusoidal endothelial cells but failure to induce differentiation toward Th1 cells. Gastroenterology 1999; 116: 1428–1440.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  111. 111

    Diehl L, Schurich A, Grochtmann R, Hegenbarth S, Chen L, Knolle PA . Tolerogenic maturation of liver sinusoidal endothelial cells promotes B7-homolog 1-dependent CD8+ T cell tolerance. Hepatology 2008; 47: 296–305.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  112. 112

    Limmer A, Ohl J, Wingender G, Berg M, Jungerkes F, Schumak B et al. Cross-presentation of oral antigens by liver sinusoidal endothelial cells leads to CD8 T cell tolerance. Eur J Immunol 2005; 35: 2970–2981.

    CAS  Article  PubMed  Google Scholar 

  113. 113

    Liu W, Tang L, Zhang G, Wei H, Cui Y, Guo L et al. Characterization of a novel C-type lectin-like gene, LSECtin: demonstration of carbohydrate binding and expression in sinusoidal endothelial cells of liver and lymph node. J Biol Chem 2004; 279: 18748–18758.

    CAS  Article  PubMed  Google Scholar 

  114. 114

    Dong H, Zhu G, Tamada K, Flies DB, van Deursen JM, Chen L . B7-H1 determines accumulation and deletion of intrahepatic CD8+ T lymphocytes. Immunity 2004; 20: 327–336.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  115. 115

    Kruse N, Neumann K, Schrage A, Derkow K, Schott E, Erben U et al. Priming of CD4+ T cells by liver sinusoidal endothelial cells induces CD25low forkhead box protein 3- regulatory T cells suppressing autoimmune hepatitis. Hepatology 2009; 50: 1904–1913.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  116. 116

    Schildberg FA, Hegenbarth SI, Schumak B, Scholz K, Limmer A, Knolle PA . Liver sinusoidal endothelial cells veto CD8 T cell activation by antigen-presenting dendritic cells. Eur J Immunol 2008; 38: 957–967.

    CAS  Article  PubMed  Google Scholar 

  117. 117

    Sato M, Suzuki S, Senoo H . Hepatic stellate cells: unique characteristics in cell biology and phenotype. Cell Struct Funct 2003; 28: 105–112.

    CAS  Article  PubMed  Google Scholar 

  118. 118

    Winau F, Hegasy G, Weiskirchen R, Weber S, Cassan C, Sieling PA et al. Ito cells are liver-resident antigen-presenting cells for activating T cell responses. Immunity 2007; 26: 117–129.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  119. 119

    Yu MC, Chen CH, Liang X, Wang L, Gandhi CR, Fung JJ et al. Inhibition of T-cell responses by hepatic stellate cells via B7-H1-mediated T-cell apoptosis in mice. Hepatology 2004; 40: 1312–1321.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  120. 120

    Yang HR, Hsieh CC, Wang L, Fung JJ, Lu L, Qian S . A critical role of TRAIL expressed on cotransplanted hepatic stellate cells in prevention of islet allograft rejection. Microsurgery 2010; 30: 332–337.

    Article  PubMed  PubMed Central  Google Scholar 

  121. 121

    Jiang G, Yang HR, Wang L, Wildey GM, Fung J, Qian S et al. Hepatic stellate cells preferentially expand allogeneic CD4+ CD25+ FoxP3+ regulatory T cells in an IL-2-dependent manner. Transplantation 2008; 86: 1492–1502.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  122. 122

    Yang HR, Chou HS, Gu X, Wang L, Brown KE, Fung JJ et al. Mechanistic insights into immunomodulation by hepatic stellate cells in mice: a critical role of interferon-gamma signaling. Hepatology 2009; 50: 1981–1991.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  123. 123

    Steptoe RJ, Patel RK, Subbotin VM, Thomson AW . Comparative analysis of dendritic cell density and total number in commonly transplanted organs: morphometric estimation in normal mice. Transplant Immunol 2000; 8: 49–56.

    CAS  Article  Google Scholar 

  124. 124

    Woo J, Lu L, Rao AS, Li Y, Subbotin V, Starzl TE et al. Isolation, phenotype, and allostimulatory activity of mouse liver dendritic cells. Transplantation 1994; 58: 484–491.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  125. 125

    Thomson AW, Lu L . Are dendritic cells the key to liver transplant tolerance? Immunol Today 1999; 20: 27–32.

    CAS  Article  PubMed  Google Scholar 

  126. 126

    Bamboat ZM, Stableford JA, Plitas G, Burt BM, Nguyen HM, Welles AP et al. Human liver dendritic cells promote T cell hyporesponsiveness. J Immunol 2009; 182: 1901–1911.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  127. 127

    Li G, Kim YJ, Broxmeyer HE . Macrophage colony-stimulating factor drives cord blood monocyte differentiation into IL-10highIL-12absent dendritic cells with tolerogenic potential. J Immunol 2005; 174: 4706–4717.

    CAS  Article  PubMed  Google Scholar 

  128. 128

    Rutella S, Bonanno G, Procoli A, Mariotti A, de Ritis DG, Curti A et al. Hepatocyte growth factor favors monocyte differentiation into regulatory interleukin (IL)-10++IL-12low/neg accessory cells with dendritic-cell features. Blood 2006; 108: 218–227.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  129. 129

    Cabillic F, Rougier N, Basset C, Lecouillard I, Quelvennec E, Toujas L et al. Hepatic environment elicits monocyte differentiation into a dendritic cell subset directing Th2 response. J Hepatol 2006; 44: 552–559.

    CAS  Article  PubMed  Google Scholar 

  130. 130

    Kingham TP, Chaudhry UI, Plitas G, Katz SC, Raab J, DeMatteo RP . Murine liver plasmacytoid dendritic cells become potent immunostimulatory cells after Flt-3 ligand expansion. Hepatology 2007; 45: 445–454.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  131. 131

    Probst HC, McCoy K, Okazaki T, Honjo T, van den Broek M . Resting dendritic cells induce peripheral CD8+ T cell tolerance through PD-1 and CTLA-4. Nat Immunol 2005; 6: 280–286.

    CAS  Article  PubMed  Google Scholar 

  132. 132

    Biswas SK, Lopez-Collazo E . Endotoxin tolerance: new mechanisms, molecules and clinical significance. Trends Immunol 2009; 30: 475–487.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  133. 133

    Khanna A, Morelli AE, Zhong C, Takayama T, Lu L, Thomson AW . Effects of liver-derived dendritic cell progenitors on Th1- and Th2-like cytokine responses in vitro and in vivo. J Immunol 2000; 164: 1346–1354.

    CAS  Article  PubMed  Google Scholar 

  134. 134

    Goubier A, Dubois B, Gheit H, Joubert G, Villard-Truc F, Asselin-Paturel C et al. Plasmacytoid dendritic cells mediate oral tolerance. Immunity 2008; 29: 464–475.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  135. 135

    Moseman EA, Liang X, Dawson AJ, Panoskaltsis-Mortari A, Krieg AM, Liu YJ et al. Human plasmacytoid dendritic cells activated by CpG oligodeoxynucleotides induce the generation of CD4+CD25+ regulatory T cells. J Immunol 2004; 173: 4433–4442.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  136. 136

    Tokita D, Sumpter TL, Raimondi G, Zahorchak AF, Wang Z, Nakao A et al. Poor allostimulatory function of liver plasmacytoid DC is associated with pro-apoptotic activity, dependent on regulatory T cells. J Hepatol 2008; 49: 1008–1018.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  137. 137

    Horstmann B, Zinser E, Turza N, Kerek F, Steinkasserer A . MCS-18, a novel natural product isolated from Helleborus purpurascens, inhibits dendritic cell activation and prevents autoimmunity as shown in vivo using the EAE model. Immunobiology 2007; 212: 839–853.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  138. 138

    Feng S . Long-term management of immunosuppression after pediatric liver transplantation: is minimization or withdrawal desirable or possible or both? Curr Opin Organ Transplant 2008; 13: 506–512.

    Article  PubMed  PubMed Central  Google Scholar 

  139. 139

    Orlando G, Soker S, Wood K . Operational tolerance after liver transplantation. J Hepatol 2009; 50: 1247–1257.

    Article  PubMed  Google Scholar 

  140. 140

    LoDuca PA, Hoffman BE, Herzog RW . Hepatic gene transfer as a means of tolerance induction to transgene products. Curr Gene Ther 2009; 9: 104–114.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  141. 141

    Kren BT, Unger GM, Sjeklocha L, Trossen AA, Korman V, Diethelm-Okita BM et al. Nanocapsule-delivered Sleeping Beauty mediates therapeutic Factor VIII expression in liver sinusoidal endothelial cells of hemophilia A mice. J Clin Invest 2009; 119: 2086–2099.

    CAS  PubMed  PubMed Central  Google Scholar 

  142. 142

    Han Q, Zhang C, Zhang J, Tian Z . Reversal of hepatitis B virus-induced immune tolerance by an immunostimulatory 3p-HBx-siRNAs in a retinoic acid inducible gene I-dependent manner. Hepatology 2011; 54: 1179–1189.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by the National Basic Research Project (973 project) (No. 2013CB944902) and the Natural Science Foundation of China (Nos. 31021061 and 91029303). We thank from Dr Fudong Shi from Tian Jing Medical University, China, for critically reading the manuscript and providing suggestions.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Zhigang Tian.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Li, F., Tian, Z. The liver works as a school to educate regulatory immune cells. Cell Mol Immunol 10, 292–302 (2013). https://doi.org/10.1038/cmi.2013.7

Download citation

Keywords

  • liver
  • immune regulation
  • immune tolerance

Further reading

Search

Quick links