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.’
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.
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 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 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+Ly6G−LY6Chigh) 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).
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 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 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
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+CD11b−SiglecH+) 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+CD8α−CD11b+) 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
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.
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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.
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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
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