Immunity, tolerance and autoimmunity in the liver: A comprehensive review

Journal of Autoimmunity xxx (2015) 1e16

Contents lists available at ScienceDirect

Journal of Autoimmunity journal homepage: www.elsevier.com/locate/jautimm

Review article

Immunity, tolerance and autoimmunity in the liver: A comprehensive review Derek G. Doherty* Division of Immunology, School of Medicine, Trinity College Dublin, Ireland

a r t i c l e i n f o

a b s t r a c t

Article history: Received 25 August 2015 Accepted 26 August 2015 Available online xxx

The hepatic immune system is constantly exposed to a massive load of harmless dietary and commensal antigens, to which it must remain tolerant. Immune tolerance in the liver is mediated by a number of specialized antigen-presenting cells, including dendritic cells, Kupffer cells, liver sinusoidal endothelial cells and hepatic stellate cells. These cells are capable of presenting antigens to T cells leading to T cell apoptosis, anergy, or differentiation into regulatory T cells. However, the hepatic immune system must also be able to respond to pathogens and tumours and therefore must be equipped with mechanisms to override immune tolerance. The liver is a site of accumulation of a number of innate lymphocyte populations, including natural killer cells, CD56þ T cells, natural killer T cells, gd T cells, and mucosal-associated invariant T cells. Innate lymphocytes recognize conserved metabolites derived from microorganisms and host cells and respond by killing target cells or promoting the differentiation and/or activation of other cells of the immune system. Innate lymphocytes can promote the maturation of antigen-presenting cells from their precursors and thereby contribute to the generation of immunogenic T cell responses. These cells may be responsible for overriding hepatic immune tolerance to autoantigens, resulting in the induction and maintenance of autoreactive T cells that mediate liver injury causing autoimmune liver disease. Some innate lymphocyte populations can also directly mediate liver injury by killing hepatocytes or bile duct cells in murine models of hepatitis, whilst other populations may protect against liver disease. It is likely that innate lymphocyte populations can promote or protect against autoimmune liver disease in humans and that these cells can be targeted therapeutically. Here I review the cellular mechanisms by which hepatic antigen-presenting cells and innate lymphocytes control the balance between immunity, tolerance and autoimmunity in the liver. © 2015 Elsevier Ltd. All rights reserved.

Keywords: Liver Immunity Tolerance Autoimmunity Antigen presentation Innate lymphocytes

Abbreviations: AIH, autoimmune hepatitis; ALD, autoimmune liver disease; APC, antigen-presenting cell; CTLA-4, cytotoxic T cell antigen-4; DC, dendritic cell; a-GC, agalactosylceramide; mDC, myeloid dendritic cells; EAE, experimental autoimmune encephalomyelitis; FasL, Fas ligand; FoxP3, forkhead box P3; HBV, hepatitis B virus; HCV, hepatitis C virus; HIV, human immunodeficiency virus; HMB-PP, (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate; HSC, hepatic stellate cell; IDO, indoleamine 2,3dioxygenase; iNKT, invariant natural killer T cell; KC, Kupffer cell; KIR, killer immunoglobulin-like receptor; IFN-g, interferon-g; IL, interleukin; LSEC, liver sinusoidal endothelial cell; MAIT, mucosal-associated invariant T cell; MDSC, myeloid-derived suppressor cell; MIC, MHC class I polypeptide-related protein; MHC, major histocompatibility complex; MR1, MHC class I-like molecule-1; MS, multiple sclerosis; NK, natural killer cell; NKT, natural killer T cell; NLR, nucleotide-binding oligomerization domain-like receptor; NOD, non-obese diabetic mouse; PBC, primary biliary cirrhosis; PD-L1, programmed death ligand-1; PGE2, prostaglandin E2; PSC, primary sclerosing cholangitis; RLR, retinoic acid inducible gene 1-like receptor; SLE, systemic lupus erythematosus; TCR, T cell receptor; TGF-b, transforming growth factor-b; Th, T helper; TNFa, tumour necrosis factor-a; TLR, toll-like ligand; TRAIL, TNF-related apoptosis-inducing ligand; Treg, regulatory T cell. * Division of Immunology, School of Medicine, Trinity College Dublin, Institute of Molecular Medicine, St. James’s Hospital, Dublin 8, Ireland. E-mail address: [email protected]. http://dx.doi.org/10.1016/j.jaut.2015.08.020 0896-8411/© 2015 Elsevier Ltd. All rights reserved.

Please cite this article in press as: D.G. Doherty, Immunity, tolerance and autoimmunity in the liver: A comprehensive review, Journal of Autoimmunity (2015), http://dx.doi.org/10.1016/j.jaut.2015.08.020

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Contents 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16.

Immunity and tolerance in the liver . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Autoimmune liver disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Immune dysregulation in autoimmune liver disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The liver sinusoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Antigen presentation to CD4þ T cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Antigen presentation in the liver . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Overriding hepatic tolerance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . NK cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CD56þ T cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . NKT cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . NKT cells in autoimmune liver disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . gd T cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . gd T cells in autoimmune liver disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . MAIT cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Concluding remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Thanks to Giorgina and Diego . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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The human liver receives approximately 1.5 L of blood every minute, from the gastrointestinal tract via the portal vein, and from the systemic circulation via the hepatic artery. This blood supply carries a massive antigenic load of harmless dietary and commensal products, to which the hepatic immune system must remain tolerant. At the same time, the hepatic immune system needs to be able to respond to a variety of blood-borne viruses, bacteria and parasites in addition to metastatic cells that frequently home from other body locations to the liver. The need for tight immune regulation, or tolerance, in the liver is provided for by an abundance of immunosuppressive cells, cytokines and ligands in the liver, that ensure that pathogen products (such as bacterial lipopolysaccharide) and antigens that are encountered in the liver generally do not stimulate immune responses [1e3]. This predominantly tolerogenic role of the hepatic immune system was first shown in 1969 by Calne and co-workers [4] who found that porcine liver allografts that were mismatched for major histocompatibility complex (MHC) antigens were frequently accepted in the absence of immunosuppression. Subsequent studies confirmed this phenomenon in other species and found that recipients of liver allografts are more likely to accept non-liver allografts from the same donor than from a third individual [5]. The liver tolerance effect may facilitate persistent infection by pathogens, such as hepatitis B and C viruses (HBV and HCV) and Plasmodium falciparum, and may support the establishment of metastatic tumours in the liver. However, immune tolerance in the liver can be efficiently broken, resulting in robust hepatic immunity against pathogens and sometimes immunemediated liver damage. Immune tolerance to self-antigens in the liver can also breakdown, leading to autoimmune liver disease (ALD). Three distinct but overlapping ALDs of humans are identified as autoimmune hepatitis (AIH), primary sclerosing cholangitis (PSC) and primary biliary cirrhosis (PBC).

and CD8þ T lymphocytes and plasma cells which recognise and destroy liver cells with the subsequent development of liver fibrosis, which can progress to cirrhosis and liver failure. The pathogeneses of these ALDs are described in many excellent reviews [6e12] and will not be discussed in detail here. Although the three diseases exhibit similarities in their pathogenesis, they differ in their patterns of liver injury. AIH is characterised by an inflammatory cell infiltrate, mainly composed of cytotoxic T cells and plasma cells, around the portal tracts which invades and causes progressive destruction of the liver parenchyma, termed interface hepatitis. In contrast, the large intra- and extra-hepatic bile ducts are targeted in PSC leading to biliary tree obliteration resulting in biliary cirrhosis and portal hypertension. In PBC, the small bile ducts are damaged leading to portal tract destruction and biliary cirrhosis. The three types of ALD can also be distinguished by their autoantibody profiles. AIH can be divided into two clinicallydistinct diseases according to the presence of either antinuclear antibodies and anti-smooth muscle antibodies, which characterise type 1 AIH (AIH-1), or anti-liver/kidney microsomal type 1 antibodies and anti-liver cytosol antibodies which are found in patients with type 2 AIH (AIH-2). In contrast, PBC patients typically have high levels of antimitochondrial antibodies, while PSC patients can have perinuclear anti-neutrophil cytoplasmic antibodies. The aetiologies of AIH, PSC and PBC are not well-understood but appear to involve a combination of genetic and environmental factors, with the strongest genetic susceptibility factors being the inheritance of allotypes of the MHC class II proteins, which present antigenic peptides to CD4þ T cells. The MHC class II allotypes DR3, DR4 and DR52a, all of which share a common amino acid sequence motif in their antigen-binding domains, are overrepresented in patients with AIH-1 [13], whereas DR7 predisposes to AIH-2 [14], DR8 confers susceptibility to PBC [15], and DR52a is overrepresented in PSC [16].

2. Autoimmune liver disease

3. Immune dysregulation in autoimmune liver disease

AIH, PSC and PBC share common pathways of immunemediated liver injury, involving the hepatic recruitment of CD4þ

ALD is characterised by hepatic infiltrates of CD4þ and CD8þ T cells, which display cytotoxicity against liver or biliary cells and

1. Immunity and tolerance in the liver

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D.G. Doherty / Journal of Autoimmunity xxx (2015) 1e16

release inflammatory cytokines, such as interferon-g (IFN-g) and interleukin-17 (IL-17) [6e12]. Normally, these effector T cells are regulated by populations of CD4þ T cells, termed regulatory T (Treg) cells, that mediate antigen-specific suppression and prevention of autoreactivity [17,18]. An imbalance between effector and regulatory T cells appears to underlie the loss of immune tolerance to selfantigens in many autoimmune diseases. Depletions of Treg cells, defined by the expression of CD4, CD25, the transcription factor forkhead box P3 (FoxP3) and low expression of CD127, have been reported in the blood and livers of patients with AIH-1, AIH-2 and with the autoimmune hepatitis-sclerosing cholangitis variant [19e23]. These depletions correlated, in some studies, with disease activity. Treg cells from AIH patients are reported to be impaired in their ability to release immunosuppressive cytokines (such as IL-10, and transforming growth factor-b, TGF-b) and to suppress proliferation and IL-17 production by CD4þCD25- T cells [19,21e24]. However, these impairments were not always seen [25,26]. Treg cells are also reported to be depleted from the blood and livers of patients with PSC [27] and PBC [28,29]. The events that lead to the breakdown of the balance between effector and regulatory T cells are poorly understood. Several studies have provided evidence of a viral or bacterial etiology in ALD and have suggested that autoimmunity may result from immune recognition of microbial peptides that display sequence similarity to autoantigenic peptides (molecular mimicry). It is also possible that ALD results from the modification of self-antigens by drugs or microorganisms making them immunogenic, or from the aberrant exposure of normally-sequestered liver antigens to the immune system, as a result of liver damage. The observations that particular MHC class II alleles predispose individuals to developing ALD [13e16] provide a strong argument that antigen presentation to CD4þ T cells is a central event in the pathogenesis. The liver is uniquely equipped with a number of antigen-presenting cells (APC) that can present antigens to CD4þ T cells leading to either adaptive immunity or tolerance. The liver also is home to a number of resident innate lymphocytes that can sense danger and selectively activate and regulate distinct effector arms of the adaptive immune response, such as those that involve T helper type 1 (Th1), Th2,

3

Th17, regulatory T (Treg) cell and antibody responses. In this article, I review the cellular mechanisms by which the hepatic innate immune system maintains the tolerogenic environment of the liver and how hepatic immune tolerance can be broken to facilitate protective immunity and autoimmunity. 4. The liver sinusoids A cartoon diagram showing the structure of a liver sinusoid is shown in Fig. 1. The antigen-rich blood from the portal vein and hepatic artery enters the liver through the portal tracts, passes through a network of vascular channels known as sinusoids, and leaves the liver via the central vein [30,31]. The hepatic sinusoids are lined with endothelial cells and flanked by plates of hepatocytes, with the space between the sinusoidal endothelium and hepatocytes termed the Space of Disse. Liver sinusoidal endothelial cells (LSEC) are highly fenestrated, which allows unimpeded flow of blood from sinusoidal blood into the Space of Disse, causing hepatocytes to be exposed to blood from both the gastrointestinal tract and the systemic circulation. The hepatic sinusoids are also abundant in cells of the innate and adaptive immune systems, including multiple types of leukocytes capable of pathogen sensing, phagocytosis, cytotoxicity, cytokine release and antigen presentation to T cells [32e35]. Parenchymal and non-parenchymal liver cells express high levels of pathogen receptors, such as toll-like receptors (TLR), nucleotide-binding oligomerization domain-like receptors (NLR) and retinoic acid inducible gene 1-like receptors (RLR), which recognise components of microorganisms that are not found in mammalian systems. Hepatocytes are primary producers of acute phase reactants such as C-reactive protein, complement proteins, serum amyloids, opsonizing proteins such as mannosebinding lectin, and cytokines such as IL-6, tumour necrosis factora (TNF-a) and transforming growth factor-b (TGF-b), which mediate inflammation and also facilitate tissue repair and regeneration [36e38]. Many of the cells residing in the liver sinusoids are capable of antigen internalisation and presentation to T cells and the release of cytokines that activate or suppress immune responses. Hepatic antigen-presenting cells (APC) are central to the

Fig. 1. The liver sinusoids. Blood enters the liver at the portal tracts, passes through a network of sinusoids and leaves the liver via the hepatic central vein. The liver sinusoids are lined by a fenestrated layer of liver sinusoidal endothelial cells (LSEC). The portal tracts and sinusoids are abundant in dendritic cells (DC), Kupffer cells (KC), natural killer (NK) cells, natural killer T (NKT) cells, mucosal-associated invariant T (MAIT) cells and gamma/delta (gd) T cells. The Space of Disse contains the hepatic stellate cells (HSC).

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tolerogenic nature of the liver by virtue of their capacity to preferentially suppress adaptive immunity by killing or inactivating T cells or by inducing maturation of naïve T cells into Treg cells that suppress CD4þ and CD8þ T cell responses. The nature of the APCs found in the liver are discussed in the following paragraphs. 5. Antigen presentation to CD4þ T cells Antigen presentation to CD4þ T cells is an essential requirement for the generation of adaptive immune responses. It typically involves the internalisation of a microorganism or protein by an APC, and its proteolytic degradation within endocytic vesicles. Peptides generated bind to newly-synthesised MHC class II molecules within a specialised endocytic compartment, and these complexes are then transported via the trans-Golgi network to the cell surface for presentation to T cells [39,40]. Allelic variation in MHC molecules confers a differential ability to bind and present particular peptides, and it is generally accepted that the MHC class II alleles that confer susceptibility to ALD code for MHC molecules that optimally bind autoantigenic peptides and present them to T cells leading to their activation. Antigen presentation to CD4þ T cells is typically mediated by ‘professional’ APCs called dendritic cells (DC) [41,42]. DC can be divided into two main classes e myeloid DC (mDC) and lymphoid or plasmacytoid e which are found throughout the body as ‘immature’ DC, and are exquisitely equipped to recognise foreign antigen by their expression of pathogen receptors, such as TLRs, NLRs and RLRs. Plasmacytoid DC generally do not function as APCs but are capable of viral recognition and the secretion of type 1 interferons that mediate antiviral immunity [43]. In contrast, mDC are well-equipped to internalise antigens by phagocytosis, pinocytosis and receptor-mediated endocytosis. Pathogen recognition and uptake results in maturation of the DC into a professional APC, which is characterised by altered adhesion molecule and chemokine receptor expression that enables the cell to leave the site of

infection and carry its internalised pathogen cargo through the lymphatic system to the secondary lymphoid tissues. The mature DC expresses high levels of MHC and costimulatory molecules, enabling it present antigenic peptides to naïve T cells leading to their activation. The immunogenic DC also secretes cytokines, such as interleukin-12 (IL-12), IL-18, IL-21 and IL-23 which promote the differentiation of the naïve CD4þ T cell into the appropriate type of effector cell to mediate adaptive immunity against the pathogen [41,42,44]. The main subsets of effector CD4þ T cells are summarized in Fig. 2. Th1 cells secrete IFN-g and TNF-a and mediate the activation of macrophages and cytotoxic cells which fight intracellular pathogens, whereas Th2 cells produce IL-4, IL-5, IL-10 and IL-13 and activate antibody responses and eosinophils and mast cells to mediate immunity against helminth pathogens and allergens. Th17 cells produce IL-17, IL-22 and IL-23 and activate neutrophil responses against extracellular bacteria and fungi [45,46]. Th1, Th2 and Th17 cells and cytokines are thought to mediate liver damage in various types of ALD in mice and humans. Antigen presentation by DC can also lead to T cell tolerance of antigen [2,3,47,48]. Like immunogenic DC, tolerogenic DC present antigenic peptides to T cells in the secondary lymphoid organs, but this is accompanied by the expression of inhibitory receptors, such as programmed death ligand-1 (PD-L1), and the release of suppressive cytokines, such as IL-10, IL-27 and TGF-b. Antigen presentation by tolerogenic DC to developing T cells in the thymus can result in T cell death by apoptosis or T cell maturation into natural Treg cells, which suppress subsequent immunity against that antigen. Antigen presentation by tolerogenic DC in the periphery can result either in T cell inactivation by anergy (associated with lack of costimulation) or in T cell exhaustion, which is characterised by the expression of the inhibitory receptors programmed death-1, cytotoxic T lymphocyte antigen-4 and/or T cell immunoglobulin mucin3. Tolerogenic DC can also drive the activation of inducible Treg cells, characterised by the expression of CD4, CD25 and FoxP3 (Fig. 2) and the release of immunosuppressive cytokines and/or

Fig. 2. Antigen presentation to CD4þ T cells. Antigen presenting cells (APC), such as dendritic cells, internalise and process exogenous antigens and present peptide fragments bound to major histocompatibility complex (MHC) class II molecules to CD4þ T cells, leading to their activation. Depending on the costimulatory signals and cytokines released by the APC, the naïve CD4þ T cell can differentiate into distinct classes of helper T (Th) cells (green arrows). Th1 cells secrete IFN-g and TNF-a and activate macrophages and cytotoxic cells which fight intracellular pathogens. Th2 cells produce IL-4, IL-5, IL-10 and IL-13 and activate antibody responses and eosinophils and mast cells to mediate immunity against helminth pathogens and allergens. Th17 cells produce IL-17, IL-17F, IL-22 and IL-23 and activate neutrophil responses against extracellular bacteria and fungi. Th1, Th2 and Th17 cells promote liver injury in various autoimmune liver diseases in mice and humans. Antigen presentation to naïve CD4þ T cells can also lead to their differentiation into regulatory T (Treg) cells which release IL-10 and TGF-b and promote IgA responses while suppressing Th1, Th2, and Th17 cell differentiation and maintaining hepatic immune tolerance (red lines). Other subsets of effector CD4þ T cells, such as Th9 and Th22 cells have also been defined based on their cytokine secretion profiles. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

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indoleamine 2,3-dioxygenase (IDO), an enzyme that catalyses tryptophan generating the immunosuppressive product kynurenine [2,3,47,48]. 6. Antigen presentation in the liver As expected from its tolerogenic function, the liver contains multiple types of APCs that are capable of antigen presentation leading to immune tolerance. Several types of DC have been described in murine and human livers. Human hepatic myeloid DC, expressing CD11b, CD11c and CD1c (also known as blood DC antigen1 or BDCA-1) resemble other mDC populations such as those found in skin, but whereas skin mDC secrete IL-12 upon exposure to LPS, liver mDC secrete IL-10 and induce IL-10 production by T cells, rather than proliferation [49,50]. This differentiation of mDC into tolerogenic APCs is promoted by the release of macrophage colonystimulating factor released by hepatic stromal cells [51]. Plasmacytoid DC, expressing the C type lectin BDCA-2 and the IL-3 receptor chain CD123, are also abundant in the liver and these cells can upregulate PD-L1 in response to TLR and NLR agonists, enabling them to release IL-27 and promote Treg cell differentiation [52,53]. In addition to mDC and plasmacytoid DC, a number of other CD11cþ DC types, including CD8aþ ‘lymphoid-related DC’ and NK1.1þ cytotoxic ‘NK-DC’, are found in mouse liver and these may also contribute to liver tolerance [3,34]. A major population of immunogenic mDC in human liver expresses CD141 and is capable of cross-presenting antigens to CD8þ T cells and producing the antiviral cytokine IFN-l [54,55]. Thus, compared to DC in other organs, liver DC are more likely to release IL-10, IL-27 and IDO and they are less likely to produce IL-12 upon ligation of their pathogen receptors and they present antigen to T cells leading to their differentiation into Treg cells [33e35]. In mice and humans, the lipid content of liver DC appears to determine whether they are immunogenic or tolerogenic, with a low lipid content favouring tolerance [56]. Antigen presentation is also a function of the liver-resident macrophage, the Kupffer cell (KC). KC express scavenger receptors, allowing them to bind and take up a diverse array of endogenous and foreign molecules [34,35]. They also express TLRs, NLRs and other pathogen receptors enabling them to sense and internalise pathogens and apoptotic cells [57]. They express high levels of MHC and costimulatory molecules and are capable of activating naïve T cells. Distinct subsets of KC, defined by their phagocytic and cytokine-producing properties, have been described [58] and these include immunogenic M1 macrophages, which secrete high levels of IL-12 and low levels of IL-10, and ‘alternatively-activated’ or ‘repair’ M2 macrophages, which produce high levels of IL-10, TGF-b and low levels of IL-12 [59]. Upon TLR ligation, KC most frequently act as M2 macrophages, producing IL-10 and TGF-b [60,61]. Although KC can function as immunogenic APCs, antigen-presentation by these cells is frequently accompanied by an upregulation of PD-L1 [62], release of IL-10 [60], TGF-b [61], prostaglandin E2 (PGE2) [63], IDO [64] and/or arginase [65] which results in the suppression of DC-mediated T cell activation and the induction of Treg cells [66,67]. KC can also express Fas ligand (FasL), which can ligate Fas on CD8þ T cells leading to their death by apoptosis [68]. In addition to myeloid cells such as DC and KC, whose functions are rooted in innate immunity, several liver parenchymal cells are capable of antigen presentation. The endothelial cells that line the liver sinusoids can express MHC and costimulatory molecules and are capable of presenting antigen to CD8þ T cells leading to tolerance [69e71] and to CD4þ T cells leading to their differentiation into Treg cells [72]. The tolerance-inducing properties of liver sinusoidal endothelial cells (LSEC) have been attributed to their ability to produce IL-10, TGF-b and PGE2 [73,74] and to upregulate

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PD-L1 [75] during antigen presentation to T cells. Hepatic stellate cells (HSC), also known as Ito cells, are also capable of expressing MHC and presenting antigens to T cells [76,77]. HSC reside in the Space of Disse around the liver sinusoids and they regulate blood flow through the sinusoids. Antigen presentation by HSC can promote allograft acceptance mediated by PD-L1 [78] and the differentiation of naïve T cells into Treg cells [79,80]. HSC can also present glycolipids to CD1-restricted T cells [76] and promote the development of myeloid-derived suppressor cells (MDSC) with potent T cell inhibitory activities [81]. Hepatocytes can induce apoptosis in CD4þ and CD8þ T cells [82,83]. Cholangiocytes can also express TLRs [84], MHC and costimulatory molecules [85], although it is not known if these cells can present antigens to T cells. 7. Overriding hepatic tolerance Since 80% of the blood that passes through the liver sinusoids comes from the gastrointestinal tract, carrying harmless dietary and commensal organism antigens, the default immune response must be tolerance, which as outlined above, is maintained by the myriad of tolerogenic APCs in the liver. However, the hepatic immune system must also be able to respond to microbial pathogens and tumours and therefore must have mechanisms to override immune tolerance and generate effective immune responses. It is likely that the mechanisms that tip the balance of hepatic tolerance towards immunogenicity are similar to those that mediate ALD. The liver is uniquely equipped with populations of cells, collectively termed innate lymphocytes, that can perform this function. Innate lymphocytes include a variety of T cells and non-T cells that respond rapidly to conserved ligands expressed by microbial pathogens, pathogen-infected cells and tumour cells. Innate lymphocytes that do not possess T cell antigen receptors (TCR) include natural killer (NK) cells and ‘innate lymphoid cells’, which mediate cytotoxicity and the secretion of cytokines that activate and polarize adaptive immune responses. Innate T cells express semiconserved TCRs, which unlike those on conventional T cells which recognize peptide fragments of protein antigens presented by MHC molecules, display specificity for non-protein antigens, including glycolipids, pyrophosphates and other metabolites produced by microorganisms or host cells under conditions of infection or tumour transformation. The liver is a site of accumulation of innate lymphocyte populations, including NK cells, CD56þ T cells, natural killer T (NKT) cells, gamma/delta (gd) T cells and mucosalassociated invariant T (MAIT) cells (Table 1). These cells can promote and regulate innate and adaptive immune responses by promoting DC maturation into APCs, antigen presentation, and the activation of CD4þ and CD8þ T cells, B cells, neutrophils and macrophages via contact-dependent interactions and the rapid secretion of cytokines. The capacity of, and requirement for, innate T cells

Table 1 Innate T cells that are present in the human liver, their T cell receptors and the ligands and antigen presenting molecules recognized. Cell type

T cell receptor

Antigen-presenting molecule

Stimulatory ligands

Type 1 NKT cell Type 2 NKT cell MAIT cell gd T cell gd T cell gd T cell gd T cell

Va24Ja18

CD1d

Glycolipids

Diverse

CD1d

Glycolipids

Va7.2Ja33 Vd1 Vd1 Vg9Vd2 Vd3

MR1 MICA, MICB, Rae1, CD1c, CD1d Butyrophilin 3A1 CD1d

Riboflavin metabolites Stress-inducible proteins Glycolipids Pyrophosphates Glycolipids

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to activate multiple effector arms of the adaptive immune response, argues in favour of a role for these cells in the breakdown of immune tolerance in the liver that leads to autoimmune disease. 8. NK cells NK cells play critical roles in innate immune responses against viruses, intracellular bacteria, parasites and tumour cells [86,87]. First described in the liver sinusoids of rats, they account for up to 50% of lymphocytes in the healthy human liver [88e90]. Human NK cells can be detected by the expression of CD56 in the absence of CD3. Two populations of NK cells have been described e those that express low levels of CD56 display potent cytotoxicity, whereas NK cells with high levels of CD56 have lower cytolytic activity but secrete large amounts of cytokines [86,87]. While CD56dim NK cells account for about 90% of peripheral NK cells, CD56dim and CD56bright NK cells are present at similar frequencies in the liver. NK cells are capable of spontaneously lysing virus-infected and tumour cells via perforin, granzyme B and TNF-related apoptosis-inducing ligand (TRAIL)-mediated induction of apoptosis [91e93]. They are also capable of killing other liver cells, including hepatocytes [91,92] and HSC [94]. NK rapidly release cytokines, such as IFN-g, TNF-a and IL-10, which polarize and regulate adaptive immune responses. They also regulate the activities of DC, KC, T cells, B cells and endothelial cells [86,87]. NK cells do not have antigen-specific receptors but they can detect changes in glycoprotein expression on target cells, that can occur during infection or tumour transformation [95,96]. Their activities are controlled by receptors that mediate cell activation or inhibition upon ligation of surface molecules on target cells, and by cytokines in the environment such as IFN-a, IL-2, IL-12 and IL-15. Human NK receptors that mediate activation include CD16, the Fc receptor for IgG, responsible for antibody-dependent cellular cytotoxicity of IgG-coated target cells, the NKG2D molecule which binds to the stress-inducible MHC class I polypeptide-related proteins A and B (MICA and MICB) or retinoic acid early inducible-1 (Rae1) molecules on target cells, and CD94/ NKG2C which binds to the non-classical MHC class I molecule HLAE. Stimulatory signals through these receptors are regulated by inhibitory signals mediated by the ligation of CD94/NKG2A by HLAE, and by the recognition of normal levels of MHC class I (HLA-A, B and C) by the killer immunoglobulin-like receptors (KIR). However, downregulation of MHC class I expression, as occurs in virusinfected and tumour cells, can remove the inhibitory signals to NK cells resulting in NK cell activation, target cell cytotoxicity and cytokine production. In addition to inhibitory KIRs, NK cells can express stimulatory KIRs and a number of other stimulatory, costimulatory, inhibitory receptors and adhesion molecules. The complex interactions between classical and non-classical MHC class I molecules and these stimulatory and inhibitory NK receptors allow NK cells to respond to tumours, metastatic cells and virally infected cells, while ignoring healthy host cells [95,96]. Hepatic NK cells are bone marrow-derived NK cells that migrate to the liver, where they complete their differentiation [97], attaining upregulated levels of perforin, granzyme B and TRAIL and enhanced killing of tumour cells compared to peripheral blood NK cells [91,98,90]. Recruitment and activation of hepatic NK cells occurs during viral infections [100] and depends on cytokines released by DC, hepatocytes and KC, such as type 1 interferons, IL12, IL-15 and IL-18 [101e106] and on cellecell contacts involving NKG2D and NKRp30 [107,108]. Once activated, hepatic NK cells kill virus-infected and tumour cells and release IFN-g and TNF-a. Activated NK cells contribute to liver injury in a number of murine models of hepatitis. Treatment of mice with the TLR ligand polyinosinic-polycytidylic acid (poly I:C) results in the accumulation and activation of NK cells in the liver, where they mediate

hepatocyte injury with a histopathology that resembles AIH in humans [91,109]. Liver disease in this model required IL-12 production by KC. In another model of fulminant hepatitis, injection of poly I:C and D-galactosamine promoted the production of TNF-a and the expression Rae1 by KC. Rae1 ligation of NKG2D resulted in activation of NK cells and the release of IFN-g which synergised with KC-derived TNF-a in driving severe liver injury [110]. NK cells also contribute to liver injury induced by exotoxin A from Pseudomonas aeruginosa (KC-mediated) [111], carrageenan [112] and adenovirus infection [113] and can kill human hepatocytes infected with HCV [114] and HBV [115]. NK cells can also inhibit liver fibrosis by killing HSC [94,116] and inhibit liver regeneration after partial hepatectomy [117]. While the above-mentioned studies in mice indicate central roles for NK cells in hepatitis, there is a paucity of knowledge available on the roles of NK cells in the pathogenesis of ALD in humans. In the first report to document NK cells in the human liver, Kaneda and co-workers [118] identified ‘pit cells’ by their characteristic electron-dense granules and rod-cored vesicles in a patient with AIH. These cells had NK activity and were found in the hepatic parenchyma in contact with degenerating and immature hepatocytes, leading the authors to suggest that they may participate in development of liver damage in AIH. Chuang and co-workers [119] first reported that NK cells with enhanced cytotoxic activity and

Antigenpresenting cells

Innate lymphocytes

HSC DC

KC

Suppressive /inactive T cells CD8+ T cell CD4+ T cell Anergic T cell

Treg cell

Immune tolerance

Effector lymphocytes

B cell

Autoimmune destruction

Liver cells Fig. 3. Innate lymphocytes may break hepatic self-tolerance leading to autoimmune liver disease (ALD). The liver contains several types of antigen-presenting cells (APC), including dendritic cells (DC), Kupffer cells (KC), liver sinusoidal endothelial cells (LSEC) and hepatic stellate cells (HSC). Antigen presentation in the liver generally leads to the generation of anergic and regulatory T (Treg) cells which help maintain hepatic immune tolerance. However, immunological self-tolerance can be overridden leading to the generation of autoreactive T cells and B cells which contribute to liver injury (red arrows). Various innate lymphocytes can promote antigen presentation (adjuvant effect), release cytokines that polarize T cell responses, and may be able to switch the tolerogenic environment of the liver to one that favours immunity. Innate lymphocytes can also kill hepatocytes and/or bile duct epithelial cells (red arrow) and may be important mediators of ALD in humans. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

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perforin expression are increased in frequency and absolute number in the blood and liver of patients with PBC. Recruitment of NK cells and T cells to the livers of these patients was mediated by chemokines, such as fractalkine, released by biliary epithelial cells [120]. NK cells isolated from patients with PBC were found to be capable of killing autologous biliary epithelial cells by a mechanism that involved TLR4 ligation on NK cells and IFN-a produced by TLR3-stimulated monocytes [121]. Increased cytotoxicity by NK cells in PBC patients may be due to upregulated TRAIL expression in these patients [122]. NK cells are also reported to be expanded in the blood [123] but not liver [88] of patients with PSC. Hepatic NK cells from patients with PSC had reduced cytotoxic activity compared to hepatic NK cells from patients with other ALD and healthy controls subjects [124]. Thus, like in murine models of ALD, NK cells are likely to directly kill liver cells in humans with PBC but not PSC. Although it has not been not tested in patients with ALD, human NK cells have the capacity to induce maturation of DC into APCs that express costimulatory molecules, release IL-12 and activate naïve T cells [125,126]. Murine NK cells can promote CD8þ T cell responses [127,128], in part by inducing cytokine release by DC [129,130] and NK cells can induce antigen cross-presentation by DC to CD8þ T cells [131,132]. It is thus possible that NK cells play a role in promoting the differentiation of DC into immunogenic APC, which could underlie the aberrant T cell activation seen in patients with ALD. This hypothesis is illustrated in Fig. 3.

9. CD56þ T cells A subset of human T cells expresses CD56 and a variable number of NK cell stimulatory and inhibitory receptors of their cell surfaces are are sometimes termed natural T cells [99,133,134]. CD56 expression by T cells confers on them the ability to be activated by TCR-independent stimuli, including cytokines and NK cell ligands, in addition to specific antigen recognised by the TCR [135e137]. CD56þ T cells express memory phenotypes and respond more rapidly than CD56- T cells to stimulation [133,137]. Compared to CD56- T cells, CD56þ T cells display enhanced cytotoxic activity against a broader range of target cell types and more rapid and potent Th1 and Th2 cytokine production [137,138]. CD56þ T cells generally account for less than 5% of peripheral T cells but they accumulate in the human liver and intestine, representing up to 50% of hepatic T cells [89,90,139]. Their numbers are altered in blood and liver of patients with viral hepatitis and hepatic malignancy [140e143]. The expression of CD56 by T cells and associated enhanced effector activities can be induced on conventional CD8þ T cells by activation in the presence of IL-2, which has led to their testing as antitumour effectors in clinical trials for various cancers [144]. The presence of these highly immunogenic T cells in immunotolerant organs, such as the liver, suggests that they may emerge in parallel with inducible Treg cells to provide a counterregulatory T cell population that can override the tolerogenic mechanisms outlined above. Little is known about the role of CD56þ T cells in ALD. They are present scattered throughout the liver parenchyma of children with type 1 AIH [145] and de novo AIH after liver transplantation [146] but appear to be depleted from the livers of adults with type 1 AIH, in particular those with active disease [21]. CD56þ T cells are expanded in the livers of patients with advanced PBC [147]. Since CD56þ T cells encompass a large variety of antigen-specific and innate CD4þ and CD8þ T cells, with diverse functions in immunity, many investigators have turned their attention to innate T cells with more defined specificities, such as NKT cells.

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10. NKT cells NKT cells are a heterogeneous group of T cells that recognise glycolipid antigens presented by the MHC class I-like molecule CD1d [148,149]. Two classes of NKT cells are found in humans and mice. Type 1 or invariant NKT (iNKT) cells express a TCR composed of an invariant TCR a-chain (Va24-Ja18 in human and Va14-Ja18 in mice) which pairs with a limited number of b-chains, whereas type 2 NKT cells express a diverse array of TCRs that recognise CD1d. Type 1 and type 2 NKT cells also express a number of NK cell stimulatory receptors, such as NK1.1 in mice and NKG2C and NKG2D in humans. The semi-invariant TCR on iNKT cells recognises a number of self [150,151] and microbial [152,153] glycosphingolipids, however, most of our understanding of NKT cells comes from studies of murine and human iNKT cells stimulated with the xenogeneic glycolipid, a-galactosylceramide (a-GC). Upon activation with a-GC in vitro, iNKT cells kill target cells and secrete a diverse range of growth factors and cytokines [148,149]. iNKT cells are notorious for their ability to produce Th1 (IFN-g and TNF-a), Th2 (IL-4, IL-5 and IL-13), Th9 (IL-9), Th17 (IL-17A and IL-22) and regulatory T cell (IL-10) cytokines, sometimes simultaneously [154,155]. Cytokines released by iNKT cells contribute to the activation of T cells [156], NK cells [156,157], macrophages [158] and suppression of functions of neutrophils [159] and MDSC [160]. Type 1 and type 2 NKT cells can influence antigen presentation by interacting with DCs. Co-culture of activated NKT cells with DC can induce the expression MHC class II, CD80 and CD86 and the release of IL-12 by DC by a mechanism that involves CD40/CD40L interactions between the two cells [161,162]. The adjuvant effect of iNKT cells for DC also occurs in vivo: a single intravenous dose of aGC stimulated the full maturation of DCs, which led to the induction of CD4þ and CD8þ T cell responses to a coadministered protein [163]. Of note, a subset of iNKT cells can also kill DCs [164]. iNKT cells can also provide help for B cell maturation and antibody production. CD1d and iNKT cells are required for the generation of protective antibody responses against microbial pathogens in murine models [165,166]. Co-administration of a-GC with immunizing antigen to mice results in enhanced production of antibodies specific for the antigen [167,168] by promoting affinity maturation and the generation of antibody-secreting plasma cells and memory B cells [168e170]. Marginal zone B cells are the most efficient B cell subset at presenting glycolipids to iNKT cells [171] and all subsets of human iNKT cells, defined by CD4 and CD8 expression (CD4þ, CD8aþ and CD4CD8a), are capable of providing B cell help for IgM, IgA and IgG production [172e174]. We have provided evidence that CD4þ iNKT cells can promote the maturation of B cells into tolerogenic APC, which express CD40, CD86 and HLA-DR but are unable to drive proliferation of autologous and alloreactive conventional T cells [174]. Therefore, different subsets of NKT cells play central roles in the activation and regulation of adaptive immune responses by directly interacting with other cell types. 11. NKT cells in autoimmune liver disease iNKT cells account for up to 50% of the hepatic T cell compartment in mice, compared to <5% of peripheral blood T cells [175,176]. In humans, iNKT cells make up 0.01e0.1% of T cells in blood and up to 2% of T cells in healthy liver, whereas most human hepatic NKT cells are type 2 NKT cells [176,177]. Expression of the chemokine receptors CXCR3 and CXCR6 is required for them to home to the liver [178,179] where they accumulate within the liver microvasculature, crawling on the luminal side of LSEC [180]. Using parabiotic mice, Thomas and co-workers [181] demonstrated that most liver NKT cells fail to recirculate, but are retained locally through

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interactions between leukocyte function-associated antigen-1 (LFA-1) and intercellular adhesion molecule-1 (ICAM-1). Hepatic iNKT cells can be activated by microbial glycolipid antigens presented by CD1d (cognate activation) or by cytokines released by myeloid cells infected with bacteria that do not contain lipids in their cell walls [152,182]. They can make CD1d-dependent interactions with hepatic DC [56], KC [183], LSEC [180], MDSC [160], stellate cells [76] hepatocytes [184] and cholangiocytes [185]. While the roles of iNKT cells in ALD are poorly understood, iNKT cells are generally thought to have protective effects against autoimmune disease. Deficiencies of IL-4- and IFN-g-producing iNKT cells have been reported in patients with type 1 diabetes [186,187], although these finding has been refuted [188,189]. iNKT cells are numerically and functionally impaired in non-obese diabetic (NOD) mice, a model of type 1 diabetes [190,191]. Restoration of iNKT cell numbers by transgenic overexpression of the Va24Ja18 TCR [190] or adoptive transfer of iNKT cells from healthy mice [192] protected NOD mice from developing diabetes. This protection was mediated in part by IL-4 production by iNKT cells [190,193] and was associated with migration of tolerogenic CD1cþ mDC to the pancreatic lymph nodes [194]. Th2-biased iNKT cell numbers are also low in patients with multiple sclerosis (MS) and they increase in patients during remission [195,196]. Similar to humans with MS, mice that are genetically susceptible to developing experimental autoimmune encephalomyelitis (EAE), such as SJL and MRL lpr/lpr mice, exhibit deficiencies of iNKT cell subsets [197,198] and these mice can be protected from developing EAE by injection of a-GC [199] or by overexpressing the Va14Ja18 TCR [198]. Furthermore, activation of iNKT cells with a synthetic glycolipid analogue of a-GC, that preferentially induces IL-4 production by iNKT cells, afforded superior protection against EAE [200]. However, other studies have shown that a-GC can also promote the development of EAE [201] and that mice deficient in IL-4, CD1d or iNKT cells have a similar disease course to wild type mice [198,199]. It is likely that iNKT cells contribute to the pathogenesis of EAE, and possibly MS, by promoting IFN-g and IL-17 production by other cells [198] but they are not absolutely required. The contribution of iNKT cells to systemic lupus erythematosus (SLE) is less clear. Patients with SLE [202,203] and lupusprone mouse strains [197,204] have reduced numbers of iNKT cells, suggesting that iNKT cells may protect against lupus. However, in other animal models CD1d and iNKT cells appear to be required for the development of lupus, which can be induced by administration of a-GC in vivo [205e207]. To date, little is known about NKT cell frequencies, phenotypes and functions in patients with ALD. In one study, iNKT cells were found to be expanded in the livers of patients with PBC compared to healthy controls [208], however, this finding was not confirmed in another study [209]. CD1d expression by cholangiocytes was also reported to be downregulated in PBC patients [185]. iNKT cells can trigger and exacerbate ALD in mice. They promote disease that resembles PBC in mice [210e212] and can promote fibrosis in many models of ALD [212e214]. In contrast, type 2 NKT cells can protect against ALD in mice [215,216]. Most of our knowledge of the cellular events that lead to AIH comes from studies on murine concanavalin (ConA)-induced hepatitis, an inflammatory liver disease that resembles AIH induced by a single intravenous injection of ConA [217,218]. An essential role for iNKT cells in the pathogenesis of ConA-induced hepatitis is evident from studies that showed that iNKT cell-deficient mice are resistant to the disease and that adoptive transfer of iNKT cells from wild type mice can sensitise susceptible mice to ConA-induced hepatitis [219]. Upon ConA administration, hepatic NKT cells rapidly upregulate FasL expression and mediate cytotoxicity. These cells also upregulate Fas leading to apoptosis of iNKT cells, prevention

of which promotes iNKT cell-mediated hepatocyte death [220]. Injection of a-GC also induces liver injury in mice by a mechanism that requires TNF-a and IL-4 [221,222]. Several other studies on animal models of AIH have demonstrated critical roles for IL-4, IFN-g and TNF-a in iNKT cell-mediated hepatocyte cytotoxicity [217,223e225], a finding which parallels observations in children with AIH [226]. Roles for IL-5 [227,228] and IL-17 [229] in the pathogenesis of iNKT cell-mediated hepatitis have also been reported, whereas other studies have found IL-15 [230] and IL-17 [231] to be protective against liver injury. iNKT cells can also mediate liver injury in Salmonella infection [232] and alcoholic liver disease [233] in mice. The above studies clearly show a pathogenic role for type 1 NKT cells in AIH in mice. If future research can confirm that iNKT cells contribute to liver damage in AIH in humans, these cells could be logical targets for therapeutic intervention. Clinical trials in humans for cancer involving the adoptive transfer of ex vivo expanded autologous DC, pulsed with a-GC, in the absence or presence of expanded iNKT cells are ongoing [234,235]. While these approaches aim to systemically activate iNKT cells, immunotherapy for AIH would more likely involve depletion or inhibition of these cells. 12. gd T cells In addition to B cells and ab T cells, gd T cells represent a third lineage of lymphocytes that express rearranged antigen receptors [236,237]. They account for 1e5% of T cells in human peripheral blood but are highly enriched in tissues, in particular the liver, intestine, skin and bronchial epithelia. In humans, most gd T cells belong to one of three groups, defined by the expression of Vd1, Vd2 or Vd3 TCR d-chains, which can pair with various g-chains. Vg9Vd2 T cells account for over 90% of gd T cells in blood, whereas Vd1 and Vd3 T cells predominate in the tissues. Vd1 T cells recognize the stress-inducible proteins MICA and MICB, which are expressed by some tumour and virus-infected cells [238], and glycolipid antigens presented by CD1c [239] and CD1d [240,241]. Their responses to TCR stimulation are also modulated by ligands for TLR1, 2, 3, 5 and 6 and from contact-dependent signals and cytokines released by DC [242]. Vd1 T cells expand in patients with intracellular bacterial infections, such as Mycobacterium tuberculosis and Listeria monocytogenes [243], fungi such as Candida albicans [244,245], viruses such as cytomegalovirus [246], HIV [247] and HBV [248], and in the autoimmune disease celiac disease [249]. T cells expressing the Vg9Vd2 TCR typically account for 1e5% of T cells in healthy adults, but they can dramatically expand in microbial infections, reaching >50% of all T cells at infected sites [250]. The Vg9Vd2 TCR recognizes a variety of low molecular weight pyrophosphate intermediates of isoprenoid biosynthesis (phosphoantigens), but the most potent phosphoantigen known is (E)-4hydroxy-3-methyl-but-2-enyl pyrophosphate (HMB-PP), an intermediate of the non-mevalonate pathway that is found in the majority of Gram-negative bacteria, some Gram-positive species and some parasites, such as P. falciparum and Toxoplasma gondii [251e253]. Vg9Vd2 T cells can also recognize isopentenyl pyrophosphate and dimethylallyl pyrophosphate, two further ‘phosphoantigens’ with bioactivities approximately 10,000-fold lower than that of HMB-PP, that are produced as intermediates of the mevalonate pathway of isopreniod synthesis, found in higher eukaryotes [252,253]. Overproduction of these metabolites as a result of a dysregulation of the mevalonate pathway, be it in metabolically active cells including tumour cells or through inhibition of farnesyl pyrophosphate synthase by aminobisphophonates such as zoledronate, is thought to render such cells targets of Vg9Vd2 T cells [254,255]. Zoledronate and related drugs are therefore receiving substantial attention as Vg9Vd2 T cell-stimulating agents for

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immunotherapies against advanced solid and hematological tumours [256,257]. Recently, butyrophilin 3A1 (CD277) was shown to bind to phosphoantigens within cells, resulting in activation of Vg9Vd2 T cells [258,259]. Activated Vg9Vd2 T cells exhibit a range of effector functions including direct cytotoxicity of infected and tumour cells, the induction of inflammatory and immunoregulatory processes and promotion of the survival, differentiation and activation of monocytes, neutrophils, dendritic cells, ab T cells and B cells [236,237,252,253]. They can bridge innate and adaptive immune responses by promoting the differentiation of a number of cell types into APCs. Importantly, Vg9Vd2 T cells, alone and in synergy with pathogen products, can induce differentiation of monocytes [260], neutrophils [261], DC [262,263] and B cells [264] into immunogenic APC that express co-stimulatory markers, produce cytokines and stimulate T cells. Vg9Vd2 T cells themselves can also act as APCs for CD4þ and CD8þ T cells [265,266]. The majority of non-Vd1 and non-Vg9Vd2 gd T cells in humans express the Vd3 TCR chain. The ligand specificities of Vd3 T cells are unknown, but a proportion of these cells are thought to recognise glycolipids presented by CD1d [267]. Vd3 T cells are reported to be expanded in peripheral blood of renal and stem cell transplant recipients with cytomegalovirus activation [246,268], in patients with HIV infection [269] and B cell chronic lymphocytic leukemia [270] and in the healthy liver [271] and intestine [249]. These cells produce multiple cytokines and possess adjuvant activity for DC, promoting their differentiation into immunogenic DC [267]. 13. gd T cells in autoimmune liver disease The healthy liver is a site of accumulation of gd T cells, many of which are capable of killing tumour cell lines and releasing IFN-g, TNF-a, IL-2 and IL-4, sometimes simultaneously [90,98,271]. The Vd1, Vd2 and Vd3 subsets of gd T cells are all found in greater numbers in liver than in blood [90,271]. The frequencies and absolute numbers of gd T cells are significantly higher in the blood and livers of patients with AIH, PSC and PBC, where they are predominantly found in the portal infiltrates and in areas of bile duct proliferation and fibrogenesis [272,273]. Analysis of the subtype distributions revealed that circulating Vd1 T cell numbers are higher and Vd2 T cell numbers are lower in patients with AIH-1 and the expanded Vd1 T cells produce IFN-g and granzyme B [21], suggesting that Vd1 and Vd2 T cells may promote and protect against ALD, respectively. Vd1 T cells that are capable of killing hepatocytes also accumulate in the livers of patients with chronic HCV infection [274,275], whereas their numbers in peripheral blood are increased in asymptomatic patients with chronic HBV infection [248] and in patients with HBV-associated acute-onchronic liver failure [276]. In contrast, Vd2 T cells can inhibit HCV replication [277] and are depleted from the blood of patients with chronic HCV infection [275,278]. Vd2 T cell numbers also correlate inversely with severity of HBV disease [248,279]. Vd1 and Vd2 T cells also appear to play roles in immunity against liver metastasis and hepatocellular carcinoma [271,280,281]. Thus, hepatic gd T cells appear to play diverse roles in liver injury associated with autoimmune and viral liver disease. Murine gd T cells expressing the Vg4 TCR chain can protect against ConA-induced hepatitis by releasing IL-17, which inhibits NKT cells [282]. Whereas IL-17 plays a critical role in the pathogenesis of liver fibrosis, through HSC activation [283,284], gd T cells protect against fibrosis by Fas-mediated killing of HSC [285]. Murine gd T cells can also mediate liver inflammation during adenovirus [286] and hepatitis virus strain 3 [287] infection. IL-10producing gd T cells can protect against CD8þ T cell-mediated liver injury during infection with L. monocytogenes [288]. In contrast, IL-17-producing gd T cells have a pathogenic role in

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Schistosoma japonicum infection [289]. Thus, like humans, mice have different populations of gd T cells that can either promote or protect against liver injury. 14. MAIT cells As mentioned above, iNKT cells account for less than 1% of human T cells in blood and up to 2% of hepatic T cells [177]. This contrasts with mice, where iNKT cells make up ~5% of peripheral and up to 50% of hepatic T cells [175,176], suggesting that iNKT cells may be more relevant therapeutic targets in mice than in humans. MAIT cells, on the other hand, are the most abundant innate T cell type in humans, accounting for up to 10% of peripheral T cells and 20e40% of liver T cells [290,291]. Human MAIT cells are defined by the expression of an invariant Va7.2-Ja33 TCR a-chain, which pairs with a limited number of b-chains and recognizes the MHC class Ilike molecule MR1 presenting bacterial-derived ligands [292,293]. MR1 and the Va7.2-Ja33 TCR are highly-conserved across animal species [294], suggesting an essential role for MAIT cells in survival. MAIT cells also express CD161, a C-type lectin also found on NK cells and some T cells, which binds to lectin-like transcript-1 (LLT-1) resulting in modulation of MAIT cell effector functions [295]. MAIT cells express CD8aa homodimers, the IL-18 receptor a-chain [296] and a number of chemokine receptors (CCR5, CCR6, CCR9 and CXCR6) that promote their recruitment to the liver, lungs and gut [290,291,297]. They notably express the transcription factor retinoic acid-related orphan receptor gt (RORgt) that controls IL-17 production and the multidrug-resistance transporter ABCB1, which confers on MAIT cells the ability to pump out drugs making them resistant to chemotherapy [292,293]. A role for MAIT cells in immunity against bacteria is evident from reports that they are absent in germ-free mice and they can be recovered by bacterial infection [298]. MAIT cells recognize and respond to monocytes and DC infected with a range of bacteria and fungi, including M. tuberculosis, S. typhimurium, E. coli, S. aureus and C. albicans [295,299,300]. However, they do not recognize all bacteria, with Enterococcus faecalis and Streptococcus pyrogenes being notable exceptions. The recognition is MR1-dependent and KjarNielsen and co-workers [301] first showed that the ligand that binds MR1 and stimulates MAIT cells is reduced 6-hydroxymethyl8-D-ribityllumazine (rRL-6-CH2OH), a vitamin B2 precursor. This discovery explains why MAIT cells can only be activated by bacteria and fungi that contain the riboflavin synthetic pathway [295,299,300]. MAIT cells can also be activated by combinations of IL-1b, IL-7, IL-12, IL-18 and IL-23 in the absence of TCR stimulation [296,302]. In contrast to other T cells MAIT cells do not proliferate in vitro in response to TCR stimulation in the presence of IL-2, IL-7 or IL-15, and therefore have proven challenging to grow in tissue culture. Activated MAIT cells produce inflammatory cytokines, including IFN-g, TNF-a, IL-17A and IL-22 and kill bacterial-infected cells using granzyme B [290,291,295,299,300]. MAIT cells are selectively recruited to the inflammed liver. Although they mainly mediate anti-bacterial immunity, they relocate from the blood to the liver in patients with chronic HCV infection [290]. They are also depleted from the blood of HIVinfected patients and do not recover during antiretroviral treatment [303,304]. Possible roles for MAIT cells in the pathogenesis of IBD, MS, psoriasis and arthritis have also been reported [305e308]. To date, only one study [309] has examined the presence of MAIT cells in the livers of patients with ALD. In this study, an infiltration of T cells was observed in the fibrotic areas of livers of patients with PSC, however, the numbers of MAIT cells remained unchanged. Thus, due to their large numbers, MAIT cells may be the most important innate T cell population in the human liver. However, future work is required to determine if these cells contribute to the

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pathogenesis of ALD. 15. Concluding remarks Innate T cells show great promise as targets for immunotherapy because they play key roles in initiating and polarizing adaptive immune responses by their ability to regulate APCs and other cells of the immune system. They can be easily expanded using conserved ligands and can be manipulated to selectively activate particular types of adaptive immune responses. Two innate lymphocyte populations, iNKT cells and Vd2þ gd T cells, are currently being targeted in clinical trials for cancer and are found to be safe but with low but promising clinical efficacy [234,235,256,257]. Future studies on the heterogeneity of innate lymphocytes in human liver, their interactions with the various types of APC that patrol the liver sinusoids, and their involvement in the pathogenesis of ALD will tell if these cells can be used as immunomodulators for the treatment of ALD. 16. Thanks to Giorgina and Diego My PhD research started in 1986 at King's College Hospital, London, under the supervision of Giorgina Mieli-Vergani and Diego Vergani who showed me the importance of studying the immune system in order to come up with ways to improve the lives of children with ALD. At this time, the MHC was at the centre of scrutiny among immunologists, as it offered explanations of how the adaptive immune system can recognize antigens and how it can tolerate self-antigens while removing pathogens. Under the guidance of Giorgina and Diego, I learnt how the MHC was of central importance in the pathogenesis of ALD. Over more than two decades since I left King's, I have watched Giorgina and Diego uncover many more features of liver immunity, tolerance and autoimmunity and I am extremely grateful to them for their insightful mentorship, which has continued to inspire me over the years. Acknowledgements Thanks also to Peter Donaldson, Cliona O'Farrelly, Con Feighery and Laura Madrigal Estebas and to my PhD students, past and present, for their discussions and experimental contributions. I thank the Irish Health Research Board, Science Foundation Ireland and the Irish Research Council for financial support. References [1] V. Racanelli, B. Rehermann, The liver as an immunological organ, Hepatology 43 (2006) S54eS62. [2] G. Tiegs, A.W. Lohse, Immune tolerance: what is unique about the liver, J. Autoimmun. 34 (2010) 1e6. [3] I.N. Crispe, Immune tolerance in liver disease, Hepatology 60 (2014) 2109e2117. [4] R.Y. Calne, R.A. Sells, J.R. Pena, D.R. Davis, P.R. Millard, B.M. Herbertson, et al., Induction of immunological tolerance by porcine liver allografts, Nature 223 (1969) 472e476. [5] V. Benseler, G.W. McCaughan, H.J. Schlitt, G.A. Bishop, D.G. Bowen, P. Bertolino, The liver: a special case in transplantation tolerance, Semin. Liver Dis. 27 (2007) 194e213. [6] C.A. Aoki, C.L. Bowlus, M.E. Gershwin, The immunobiology of primary sclerosing cholangitis, Autoimmun. Rev. 4 (2005) 137e143. [7] A.J. Czaja, M.P. Manns, Advances in the diagnosis, pathogenesis, and management of autoimmune hepatitis, Gastroenterology 139 (2010) 58e72. [8] G. Mieli-Vergani, D. Vergani, Unique features of primary sclerosing cholangitis in children, Curr. Opin. Gastroenterol. 26 (2010) 265e268. [9] R. Liberal, C.R. Grant, G. Mieli-Vergani, D. Vergani, Autoimmune hepatitis: a comprehensive review, J. Autoimmun. 41 (2013) 126e139. [10] J.E. Eaton, J.A. Talwalkar, K.N. Lazaridis, G.J. Gores, K.D. Lindor, Pathogenesis of primary sclerosing cholangitis and advances in diagnosis and management, Gastroenterology 145 (2013) 521e536. [11] E. Liaskou, G.M. Hirschfield, M.E. Gershwin, Mechanisms of tissue injury in

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