Journal of Hepatology
Volume 34, Issue 1 , Pages 156-160, January 2001

Dendritic cells: regulators of hepatic immunity or tolerance?

  • Derek G Doherty

      Affiliations

    • Institute of Immunology, Department of Biology, National University of Ireland Maynooth, Maynooth, Co. Kildare, Ireland
    • Corresponding Author InformationCorresponding author. Tel.: +353-1-708-3856; fax: +353-1-708-3845
    • ,
  • Cliona O'Farrelly

      Affiliations

    • Education and Research Centre, St. Vincent's University Hospital and Conway Institute, University College Dublin, Ireland

Received 17 August 2000; accepted 22 August 2000.

See Article, pages 61–67

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1. Introduction 

The liver has a uniquely specialised immune system. On one hand it is capable of responding to danger, having multiple populations of effector lymphocytes that can effectively recognise and eliminate a diversity of pathogenic microorganisms, toxins and tumours [1]. At the same time, liver defence mechanisms are so tightly regulated that the induction of tolerance is favoured over the induction of immunity. Administration of antigens via the portal vein is more likely to lead to anergy or tolerance than systemic administration of antigen and allogeneic liver transplantation across incompatible major histocompatibility complex (MHC) barriers is often successful without the need for immunosuppression [2], [3]. Thus, local immune responses are actively regulated in the liver, presumably to maintain immune tolerance to harmless self, dietary, and commensal organism antigens that arrive from the circulation via the hepatic artery and from the gastrointestinal tract via the portal vein. The mechanisms responsible for maintaining the fine balance between immune responsiveness and non-responsiveness in the liver are largely unknown but are likely to depend on the nature of the antigen, the responding cell, and the presence of cytokines and accessory molecules in the microenvironment. A key component of this orchestration is the way in which an antigen is presented to the responding lymphocyte and recent evidence suggests that the liver has a unique repertoire of antigen presenting cells (APC). In this issue of the Journal of Hepatology, Abe and colleagues [4] investigate the potential tolerogenic or immunogenic roles of murine hepatic dendritic cells (DC) and provide experimental evidence that, in contrast to other APC populations in the liver, which can induce immune tolerance, DCs are potent immunogenic APCs. These findings are of interest in the light of other studies that have shown a tolerogenic role for hepatic DCs, and have important implications for the development of strategies for manipulating the balance between immunity and tolerance such as in the prevention of infectious and immune-mediated diseases of the liver, hepatic malignancy, and allograft rejection.

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2. Antigen presentation to T cells 

APCs capture, process, and display antigens to T lymphocytes leading either to their differentiation into effector cells capable of cytotoxicity and/or cytokine secretion, or to their inactivation by apoptosis or anergy [5], [6]. While B lymphocytes can directly recognise native antigens through their B cell receptors, T cells need the antigen to be processed and presented to them by the APC. Most T cells recognise peptide fragments of protein antigens presented in the groove of APC-bound MHC molecules: MHC class I molecules generally present peptides derived from intracellular proteins to CD8+ cytotoxic T cells while MHC class II molecules generally present peptides derived from internalised antigens to CD4+ helper T cells. Naı̈ve T cells have not yet encountered specific antigen and can only be activated by ‘professional’ APCs: cells that can process antigens and express MHC class I and class II molecules, the lymphocyte costimulatory molecules CD40, CD80 (B7-1), CD86 (B7-2), and the adhesion molecules CD58 (LFA-3) and CD54 (ICAM-1) that promote physical interactions with lymphocytes [5], [6]. Completion of this immunological synapse (Fig. 1) results in the proliferation and maturation of a naı̈ve T cell into an antigen-specific effector cell with committed functions such as cytotoxicity and/or secretion of Th1 cytokines that promote cell-mediated immune responses, or Th2 cytokines that activate humoral responses [7]. An important distinction between naı̈ve and effector T cells is that naı̈ve T cell activation is dependent on antigen presentation by a professional APC whilst effector T cell activation occurs upon cognate recognition of the peptide/MHC complex only [5], [6]. Effector cell activation and function lasts for about 7–30 days and is followed by a period of cell death in which most (>95%) of the activated T cells undergo apoptosis and effector activity subsides as the amount of antigen declines. A fraction of effector T cells further mature into memory T cells which can persist in the circulation for many years and upon secondary exposure to the same antigen, can give an accelerated response [8]. Activation of memory T cells is thought to require antigen presentation by professional APCs.

  • View full-size image.
  • Fig. 1. 

    Molecular interactions that mediate naı̈ve T lymphocyte activation by professional antigen presenting cells (APCs). Antigen recognition is mediated by ligation of the T cell receptor (TCR) and the CD4 or CD8 coreceptor with a peptide/major histocompatibility complex (MHC) on the surface of the APC. Costimulation of T cell activation generally involves the ligation of CD28 on the T cell with CD80 (B7-1) or CD86 (B7-2) on the APC. Ligation of the TCR is associated with upregulation of CD154 expression by the T cell which binds to CD40 on the APC, thereby increasing expression of CD80 and CD86. Non-specific interactions between the adhesion molecules CD54 (intracellular adhesion molecule-1 or ICAM-1) on the APC and CD11a/CD18 (lymphocyte function antigen-1 or LFA-1) on the T cell and between CD58 (LFA-3) on the APC and CD2 on the T cell strengthen the physical association between the two cells. T cell activation results in the upregulation of cytotoxic T lymphocyte antigen-4 (CTLA-4) which competes with CD28 for CD80 and CD86 binding and downregulates T cell activation. Antigen-specific interactions with APCs lacking costimulatory or adhesion molecules can result in inactivation of naı̈ve T cells by anergy, whereas effector T cells have do not need costimulation for their activation.

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3. Antigen presentation in the liver 

The liver contains multiple types of APC. Liver sinusoidal endothelial cells (LSEC) line the liver sinusoids separating the parenchymal hepatocytes from the blood and thus sequester the liver matrix from the immune system [9]. Kupffer cells (KC) are the resident macrophage population of the liver which patrol the sinusoids and rapidly phagocytose and eliminate particulate antigens and pathogens entering the liver in portal venous blood [9]. DCs reside around the portal tracts and central veins and have the unique ability to capture antigens at the site of encounter and bring them to the lymphoid tissues for presentation to lymphocytes [10], [11]. Hepatocytes can also act as APCs in certain situations [12]. LSECs, KCs and DCs can efficiently internalise antigens by phagocytosis, receptor-mediated endocytosis or pinocytosis [6], [9], [11]. LSECs and KCs express antigen presenting, costimulatory and adhesion molecules and secrete interleukin-1 (IL-1) and interferon-γ (IFN-γ) suggesting that they are mature differentiated APCs [13], [14]. KCs can secrete IL-12 in response to bacterial and tumour antigens, which induces the activation of innate immune responses involving natural killer cells and natural T cells [15]. Hepatic DCs include cells of both myeloid and lymphoid lineages which are predominantly present as immature DC progenitors, expressing MHC class I and class II molecules but not the costimulatory molecules required for naı̈ve T cell activation [11]. Liver-derived DC progenitors can prolong allograft survival, and are therefore thought to play a role in the immune privilege of the liver [16].

DCs are the most efficient of APCs [6]. They are located throughout most body tissues as immature progenitors which lack the requisite signals for T cell activation, but are exquisitely well equipped to capture, internalise and process antigens for presentation by MHC molecules. Upon antigen encounter, DCs migrate to the lymphoid tissues where they complete their maturation, attract lymphocytes by releasing chemokines, and optimise the clonal selection of CD4+ or CD8+ T cells which are found in extremely low frequencies. Mature DCs are the most efficient stimulators of naı̈ve T cells, having optimal shape and high levels of expression of adhesion molecules, MHC and costimulatory receptors. They resist the suppressive effects of IL-10 and synthesise high levels of IL-12 that enhance innate immunity. Once activated by DCs, naı̈ve T cells mature into cytotoxic, Th1, or Th2 effector cells which can complete the immune responses required for the elimination of the antigen-bearing agent [6], [11].

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4. Induction of tolerance by hepatic antigen presenting cells 

Recent evidence suggests that LSECs, KCs and DCs, can differentially mediate T cell activation or inactivation. LSECs and KCs can present portal venous antigens to CD4+ T cells without the need for further maturation, but while they induce T cell proliferation and cytokine production in vitro, they fail to induce differentiation to Th1 cells [17]. Consequently they do not promote hepatic inflammation in vivo. Instead, these APCs produce IL-10, prostanoids and transforming growth factor-β in response to physiological concentrations of antigens such as bacterial lipopolysaccharide which downregulate T cell activation thus promoting local immune tolerance [9], [18], [19]. There is also evidence that KCs and LSECs can induce apoptosis of T cells in the liver [9]. The third type of hepatic APC, the DC, is also thought to be able to induce T cell tolerance. DCs are the main tolerogenic APCs in the thymic medulla and are responsible for the deletion by apoptosis of self-reactive T cells during T cell repertoire selection [6]. In the lymphoid organs, DCs can inactivate self-reactive T cells by inducing anergy or apoptosis [6], [20]. Thus, the signals received from the DC are critical determinants of whether a T cell is activated, inactivated by anergy, or deleted by apoptosis.

The nature of the signals that determine whether a DC is immunogenic or tolerogenic are under intense scrutiny. Both the nature of the antigen and the presence or absence of accessory molecules on the APC are important [6], [20]. The types of cytokines secreted during the early stages of a primary immune response also have a critical role in determining whether naı̈ve T cells are activated or tolerised as well determining whether they differentiate into Th1 or Th2 effector cells [21], [22]. The production of IL-12 by DCs induces the development of naı̈ve T cells into IFN-γ-producing Th1 cells, whereas in an IL-4-rich environment DCs induce T cells to differentiate into Th2 cells that secrete IL-4, IL-5, IL-10 and/or IL-13 [21], [22]. On the other hand, IL-10 production by DCs is associated with the development of either Th2 cells or IL-10-secreting regulatory Tr1 cells which exhibit tolerogenic properties [22]. IL-10 downregulates the expression of CD80 and CD86 on DCs and inhibits IL-12 production thus rendering them unable to activate naı̈ve T cells [18], [22].

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5. Hepatic dendritic cell precursors as immunogenic antigen-presenting cells 

The experiments of Abe et al. [4] address the phenotypic and functional maturity of murine hepatic DCs and their role in the initiation of alloreactive and antigen-specific T cell responses. After culturing non-parenchymal cells isolated from the liver with granulocyte-macrophage colony stimulating factor, a method known to promote the differentiation of monocytes into DCs, they obtained immature myeloid DCs expressing low levels of MHC class II and CD86 and demonstrating high endocytic capabilities and low allostimulatory capacity. In contrast, spleen DCs prepared in a similar manner had mature DC phenotypes, expressing high levels of MHC class II and CD86, being less efficient at particle endocytosis and exhibiting potent allostimulatory activity in the mixed lymphocyte reaction (MLR). Allostimulatory activity of hepatic DC progenitors was not induced by the addition of the proinflammatory cytokines IFN-γ and tumour necrosis factor-α (TNFα) but was induced by the addition of antigens. Pulsing of cultured hepatic DC progenitors for 48 h with type 1 collagen, hepatitis B surface antigen (HBsAg) or keyhole limpet haemocyanin (KLH) resulted in the upregulation of MHC class II and CD86 and the induction of allostimulatory activities comparable to those of spleen DCs. Pulsing of hepatic DC progenitors with HBsAg or KLH also resulted in their maturation into DCs capable of activating HBsAg-specific and KLH-specific memory T cells in proliferation and cytokine release assays. T cell activation by mature hepatic DCs required the presence of both antigen and antigen-specific memory cells. The specificity of antigen presentation was not investigated by testing whether HBsAg-pulsed DC could stimulate KLH-specific T cells and vice versa, however, antigen-stimulated DC progenitors were able to stimulate alloreactive T cells. This indicates that DC activation by antigen is not antigen-specific and results in the generation of mature DCs capable of activating T cells with distinct antigen specificities. In contrast to LSECs and KC, which produce IL-10 and fail to induce Th1 effector cell differentiation [17], [18], [19], presentation of antigen by hepatic DC progenitors to memory T cells in vitro resulted in the secretion of high levels of IFNγ (presumably by the T cell) and IL-12 (presumably by the DC) but very low levels of IL-10 [4]. Thus, while LSECs and KCs can present antigen leading to T cell tolerance, Abe et al. found that hepatic DC progenitors are similar to DC populations found in other non-lymphoid tissues in that they are present as non-immunogenic precursors that, upon encounter with antigen, mature into immunogenic APCs for memory T cells.

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6. Hepatic dendritic cell progenitors as tolerogenic antigen presenting cells 

While the above-described experiments demonstrate that mature DCs can function as immunogenic APCs in the liver, a recent study by Khanna and colleagues [23] has shown that hepatic DC progenitors may be tolerogenic APCs. Similar to the results of Abe et al. [4], these investigators found that murine liver DC progenitors induced minimal proliferation, IFN-γ production, and cytotoxic responses in allogeneic T cells compared to bone marrow-derived DCs. However, liver DCs progenitors but not bone marrow DCs produced large amounts of IL-10 in the primary MLR, a function not tested by Abe et al. [4]. Furthermore, injection of either hepatic DC progenitors or bone marrow DCs into allogeneic mice resulted in their migration to the draining lymph nodes and spleen where liver DC progenitors induced IL-10 and IL-4 production by mononuclear cells, whereas bone marrow DCs induced IFN-γ production [23]. Thus, while Abe et al. [4] have shown that mature hepatic DCs can act as immunogenic APCs in vitro, Khanna et al. [23] have shown that mature hepatic DCs are tolerogenic in vivo.

The results of Abe et al. [4] and Khanna et al. [23] at first appear somewhat contradictory. Both groups of workers report that liver DC progenitors are non-immunogenic APCs for naı̈ve T cells. However, Abe et al. [4] found that hepatic DC progenitors can be induced by antigen to mature in vitro into immunogenic APCs, producing IL-12 and capable of stimulating memory T cells to produce IFN-γ. In contrast, Khanna et al. [23] reported that hepatic DC progenitors are induced by primary stimulation to mature in vivo into tolerogenic APCs capable of stimulating the expansion of IL-10-producing Th2 and Tr1 cells. These opposite effects are reflective of the experimental design of the two studies, which when considered in the light of each other, identify fundamental clues regarding the mechanisms by which hepatic DCs can selectively induce immunity or tolerance in the liver.

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7. Functional heterogeneity of hepatic dendritic cells 

Two differences in the experimental strategies employed in the above-described experiments reveal important clues to how hepatic DC progenitors may selectively induce T cell responsiveness (immunity) or non-responsiveness (tolerance). Firstly, for the in vitro detection of the cytokines produced upon T cell activation by hepatic DC progenitors, Khanna et al. [23] used alloreactive spleen cells from MHC-dissimilar mice, while Abe et al. [4] used memory T cells taken from antigen-injected syngeneic mice. These memory T cells had previously encountered the specific antigen in vivo in the context of a professional APC, presumably one other than a liver DC progenitor. As naı̈ve T cells, they were primed to produce the Th1 cytokine, IFN-γ, and this cytokine secretion profile was retained upon secondary stimulation with a hepatic DC progenitor presenting the same antigen. However, hepatic DC progenitors were not capable of stimulating unprimed alloreactive T cells in both studies and the report by Khanna et al. [23] further demonstrates that this mechanism of tolerance induction is via the production of IL-10. This is in contrast to DCs from bone marrow and spleen (used as positive control DC populations in the above studies) which readily activated unprimed alloreactive T cells. Thus, unlike bone marrow and spleen DCs, hepatic DC progenitors induce tolerance to T cells that have not previously been primed with specific antigen, but they are potent activators of memory T cells [4], [23].

A second important observation of Abe et al. [4] is that while hepatic DC progenitors were unable to stimulate alloreactive T cells in the primary MLR, pre-pulsing of these cells with type 1 collagen, HBsAg or KLH antigens in vitro induced their maturation into DCs that were now capable of activating unprimed alloreactive T cells. Thus, while liver DC progenitors are tolerogenic in the primary T cell response, they can be induced by the addition of certain antigens in vitro to be immunogenic stimulators of unprimed alloreactive T cells.

What are the signals that transform hepatic DC progenitors that were tolerogenic for unprimed T cells into immunogenic APCs? Abe et al. [4] showed that DC maturation into APCs strictly required the presence of antigen, since even IFN-γ or TNF-α treatment did not induce allostimulatory activity in the absence of antigen. Antigen internalisation is known to trigger DC progenitors to migrate to the lymph nodes where they mature into functional APCs [6]. In this respect, Khanna et al. [23] noted that hepatic DC progenitors primed against alloreactive T cells migrate to the lymph nodes and induce tolerance, however, Abe et al. [4] found that antigen-primed hepatic DC progenitors matured in vitro into immunogenic APCs. These differences in DC function probably relate to the nature of the environment in which T cell activation takes place. DC progenitors probably are constantly exposed to, but remain tolerant of, antigens entering the liver in portal blood, yet type 1 collagen, HBsAg and KLH, effectively induced their expression of MHC class II and CD86 and their maturation into immunogenic DCs in vitro [4]. A role for the microenvironment is evident from previous reports that the extracellular matrix proteins, with which DCs are spatially associated in the liver and in lymph nodes, can induce DC maturation [24] and Thomson et al. [11] have speculated that intrahepatic contact with extracellular matrix proteins may provide signals that promote or control DC maturation. Therefore, hepatic DCs exhibit a plasticity of APC functions that are controlled at the level of the maturational status of both the DC and the T cell, and appear to be influenced by the presence and nature of antigen as well as cytokines and other cells in the microenvironment of the liver and subsequently the lymph nodes.

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8. Dendritic cells and disease 

The above-described observations indicate that the three different APC types in the murine liver can selectively induce T cell immunity or tolerance, thus ensuring that the hepatic immune system can efficiently activate the immune system against pathogens and tumours whilst remaining tolerant of harmless dietary and commensal organ antigens. This heterogeneity of APC populations reflects the unique repertoire of lymphocytes found in the liver that recognise a diversity of antigen types and antigen-presenting molecules [1], [25], [26] and the accumulation of such liver-resident cells will be controlled by chemokines, cytokines and adhesion molecules. Other tolerogenic DC populations that produce IL-10 are found at mucosal sites such as the respiratory tract [27] and the Peyer's patches of the intestine [28], while DCs isolated from the spleen and bone marrow are generally of the IL-12-secreting immunogenic type [4], [6], [23]. These findings highlight the DC system as a logical target for immune intervention for the treatment of clinical conditions that involve T cells, such as resistance to infection and tumours, autoimmune disease, allergy, immunodeficiency, organ transplantation and vaccine development. Many autoimmune and allergic conditions are associated with increased numbers of activated DCs, while tumours appear to be able to suppress DC function [6]. Therapeutic control of these diseases could involve strategies that downregulate or promote DC activation [29], [30]. Successful elimination of infectious agents requires an appropriate balance between cell-mediated (Th1) and antibody-mediated (Th2) responses [7] which appears to be controlled by the DC and is dependent on the amount and nature of the antigen, its route of entry to the body, and whether it manifests itself intracellularly or extracellularly [6]. Therefore, effective vaccine design needs to consider the nature and location of the DC, as well as the antigen and the responding lymphocyte. Finally, DCs are thought to be the instigators of both allograft rejection and tolerance [16]. The liver is generally regarded as the least immunogenic of transplanted organs with HLA matching offering little improvement in graft survival and liver transplantation can protect other organs against rejection [3]. This capacity to induce donor-specific tolerance has been attributed to donor hepatic DCs which migrate from the liver and populate peripheral host tissues where they induce tolerance of recipient alloreactive T cells [11], [16]. In conclusion, immunology and immunotherapy which have long been focused on antigens and lymphocytes, need in the future to include the DC system as an essential initiator and regulator of immune responses.

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Acknowledgements 

This work was supported by a grant from the Irish National Liver Transplant Centre. Thanks to Dr John E. Hegarty for helpful discussions.

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PII: S0168-8278(00)00020-9

doi:10.1016/S0168-8278(00)00020-9

Journal of Hepatology
Volume 34, Issue 1 , Pages 156-160, January 2001

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