The liver as a lymphoid organ annu rev

ANRV371-IY27-06 ARI 16 February 2009 9:31

The Liver as aLymphoid OrganIan Nicholas CrispeDavid H. Smith Center for Vaccine Biology and Immunology, Aab Institute for BiomedicalResearch, University of Rochester Medical Center, Rochester, New York 14642;email: nick [email protected]

Annu. Rev. Immunol. 2009. 27:147–63

The Annual Review of Immunology is online atimmunol.annualreviews.org

This article’s doi:10.1146/annurev.immunol.021908.132629

Copyright c© 2009 by Annual Reviews.All rights reserved

0732-0582/09/0423-0147$20.00

Key Words

antigen presentation, hepatitis, Kupffer cells, innate immunity,sinusoid, stellate cells

AbstractThe liver receives blood from both the systemic circulation and theintestine, and in distinctive, thin-walled sinusoids this mixture passesover a large macrophage population, termed Kupffer cells. The expo-sure of liver cells to antigens, and to microbial products derived from theintestinal bacteria, has resulted in a distinctive local immune environ-ment. Innate lymphocytes, including both natural killer cells and naturalkiller T cells, are unusually abundant in the liver. Multiple populationsof nonhematopoietic liver cells, including sinusoidal endothelial cells,stellate cells located in the subendothelial space, and liver parenchymalcells, take on the roles of antigen-presenting cells. These cells presentantigen in the context of immunosuppressive cytokines and inhibitorycell surface ligands, and immune responses to liver antigens often re-sult in tolerance. Important human pathogens, including hepatitis Cvirus and the malaria parasite, exploit the liver’s environment, subvertimmunity, and establish persistent infection.

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sinusoid: thin-walledblood space throughwhich blood passes inthe liver

Kupffer cell:intravascularmacrophage lining theliver sinusoids

DC: dendritic cell

TLR: Toll-likereceptor

APC: antigen-presenting cell

INTRODUCTION

The liver stands at a hemodynamic confluence.In distinctive, thin-walled vessels termed sinu-soids, oxygenated blood from the arterial sys-tem mixes with portal venous blood return-ing from the intestine. The sinusoids containa diversity of immunologically active cell types,including both lymphocytes and myeloid cells(Figure 1). The Kupffer cells form a large in-travascular macrophage bed and, with liver den-dritic cells (DCs), come in both immunogenicand tolerogenic forms. The liver also containsdiverse lymphocytes, including T cells, naturalkiller T (NKT) cells, and natural killer (NK)cells.

Portal venous blood contains the productsof digestion, along with antigens and micro-bial products that originate from the bacte-ria in the small and large intestine. Among

KC

HSC

LSECLSEC

mDC/pDC

Hepatocytes

Figure 1Antigen-presenting cells (APCs) in liver sinusoids. The liver contains multiplesubsets of dendritic cells, including myeloid and plasmacytoid dendritic cells(mDCs and pDCs). There are abundant mononuclear phagocytes in the formof Kupffer cells (KCs), and these can express costimulatory molecules. Inaddition, there are two additional populations of APCs in the form of liversinusoidal endothelial cells (LSECs) and hepatic stellate cells (HSCs). Theevidence for APC function in each of these cell types is summarized in the text.

these bacterial products is lipopolysaccharideendotoxin (LPS), derived from the cell walls ofGram-negative bacteria. Under normal condi-tions, LPS is undetectable in the systemic cir-culation, but it is present at up to 1.0 ng/mlin portal venous blood (1). The cells of thehepatic sinusoids express the LPS receptor andeffectively remove this molecule so that thesystemic circulation is protected from endo-toxemia (2). Many cells of the innate immunesystem express the LPS receptor, which con-sists of Toll-like receptor-4 (TLR4) togetherwith the molecules CD14 and MD2; engage-ment of this receptor on most cell types deliv-ers a strong activating signal. However, in theliver these receptors are continuously exposedto low levels of LPS, resulting in altered re-sponsiveness to an LPS challenge. At the sametime, the adaptive immune cells of the liver areexposed to food-derived antigens, the majorityof which are harmless. The continuous pres-ence, under normal conditions, of both TLRligands and antigens has resulted in a distinctiveset of mechanisms to maintain self-toleranceyet deliver immunity to infection. Liver im-munity features a local concentration of over-lapping innate immune mechanisms, togetherwith the capacity of unusual cell types to actas antigen-presenting cells (APCs). The liver’sresident immune cells are not passive in the faceof continuous exposure to antigens and LPS;instead they exist in a state of active tolerance,which results in liver allograft tolerance (3) butalso creates a window of vulnerability for well-adapted pathogens. This state of tolerance ismetastable; the right combination of signals canreverse tolerance and activate immunity locally.

INNATE IMMUNITYIN THE LIVER

The LPS from intestinal bacteria is not the onlyimmune stimulus to which the liver is exposed.Pattern-recognition receptors in the liversense the presence of enteric pathogens. Theseinclude cell surface and endosomal TLRs, cy-toplasmic nucleotide-binding oligomerization

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domain (NOD)-like receptors, and RNAhelicases, including retinoic acid inducibleprotein-I (RIG-I). The TLRs recognize adiverse array of bacterial and viral molecules,including bacterial lipopeptides (heterodimersof TLR1 and TLR2, and of TLR2 withTLR6); LPS and flagellin (TLR4 and TLR5,respectively); and exogenous dsRNA, viralssRNA, and bacterial unmethylated DNA(TLR3, TLR7, TLR8, and TLR9). The NODreceptors recognize bacterial peptidoglycans,whereas the RIG-I molecules recognizestructural features of viral ssRNA. Thesereceptors, their specificity, and their roles inhost defense were recently reviewed (4, 5).From the perspective of a global discussion ofliver immunity, the key point is that signalsfrom these diverse receptors converge on twosignaling pathways. Thus, all of the TLRsexcept TLR3 transmit signals via the adaptorprotein MyD88 (myeloid differentiationfactor-88), which results in the activation of thekinases p38, JNK, and IκB kinase, leading toNF-κB activation. NOD receptors also activateNF-κB. The TLR4 receptor complex, in ad-dition to activation via MyD88, recruits theadaptor protein TRIF (TIR-domain containingadaptor recruiting interferon-β), which acts viaTBK1 (TRAF family member–associated NF-κB activator–binding kinase 1) to cause phos-phorylation and nuclear localization of IRF-3(IFN regulatory factor 3), the transcriptionfactor that drives synthesis of type 1 interferon(IFN). Ligation of TLR3 selectively activatesthis signaling pathway. Similarly, RIG-I andits homolog MDA-5 promote the activationof mitochondrial IPS-1 (IFN-β promoterstimulator 1), resulting in IRF-3 activationand type 1 IFN secretion. These pathwaysare optimized such that pattern-recognitionreceptors engaged by bacterial products gener-ally promote NF-κB activation, whereas thosepathways activated by viral infection stronglyinduce IFN-β. The continuous, low-levelstimulation of the former pathway is one of thedistinctive features of the liver environment(Figure 2).

HBV: hepatitis B virus

NK cells are present at higher frequency inthe liver than in most tissues. Thus, in humanliver leukocytes obtained by elution from donorlivers (6), in cell suspensions obtained from hu-man liver tissue (7), and in the cells isolatedfrom the mouse liver by enzymatic digestion(8), NK cells make up as many as 50% of liverlymphocytes. Similarly to NK cells elsewhere,these cells respond both to cytokine activationand to engagement of an excess of activatingreceptors over inhibitory receptors (9). Onceactivated, they manifest their function throughcytokine synthesis and cytotoxicity. NK cells ex-press two key adaptor molecules: DAP10 andDAP12. DAP10 associates with the activatingNKG2D receptor, and the ITAM (immunore-ceptor tyrosine-based activation motif)-bearingDAP12 adaptor protein associates with severalreceptors, including the CD94-NKG2C het-erodimer and the Ly49H receptor. Ligands forNKG2D are expressed in the liver under di-verse circumstances. Low amounts of NKG2Dligands are expressed constitutively in the liver(20), and these ligands can be upregulated af-ter viral infection or transformation of hepato-cytes. The NKG2D ligands include MHC classI–related proteins A and B (MICA and MICB),which are expressed on human hepatocellularcancer cells (10), and mouse retinoic acid earlyinducible-1 (RAE-1), which is transcription-ally upregulated by cytomegalovirus infection(11). Liver NK cells are induced to synthesizeIFN-γ in response to IL-12 (12) and to manifestperforin-dependent cytotoxicity in response tothe Kupffer cell–produced cytokine IL-18 (13).They are also cytotoxic owing to the expressionof TRAIL (TNF-receptor apoptosis-inducingligand), which can engage death receptors thatare induced on hepatocytes by hepatitis B virus(HBV) (14).

The liver lymphocytes also contain an un-usually high frequency of NKT cells. Theseinclude both canonical NKT cells expressingan invariant T cell receptor (TCR) that bindsto CD1d complexed with α-galactosylceramideand the noncanonical NKT cells that recognizeother ligands. Liver NKT cells are abundant

www.annualreviews.org • The Liver as a Lymphoid Organ 149

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Constitutively engagedby gastrointestinal ligands

LPS dsRNA Viral ssRNAFlagellinBacteriallipopeptides

Bacterial peptidoglycans

TLR4TLR5TLR1/2TLR2/6

Constitutively quiescent,activated by virus infection

TLR3

IRF-3

RIG-1 MDA-1

MyD88

TRIF

NOD-1NOD-2

NF-κB

IL-10 TNF-α, IL-1,IL-6, IL-12, IL-18

IFN-αIFN-β

IPS-1

Figure 2Effects of microbial products. The model explains the effects of the liver environment on pattern-recognition receptors. The presence of detectable LPS in portal blood suggests that other gut-derivedmicrobial molecules may be present also. We therefore propose the model that NOD proteins and thesubsets of TLRs that recognize microbial products are constitutively engaged in the liver. In contrast,receptors for viral elements (TLR3, RIG-I, MDA-1) are not engaged under normal conditions. We proposethat this changes the balance between NF-κB and IRF-3-dependent signaling pathways. In this diagram,heterodimeric TLRs are indicated as TLR1/2 and TLR2/6.

HCV: hepatitis Cvirus

both in mouse (15) and in human (6). Thesecells were recently filmed patrolling the hep-atic sinusoids, based on their expression ofa GFP reporter molecule driven by the en-dogenous CXCR6 promoter (16). Despitetheir thymic origin (17) and expression of aTCRαβ generated by V(D)J recombination,these CD1d-reactive T cells show evolutionaryconvergence with leukocytes expressing innatepattern-recognition receptors; their TCRs rec-ognize glycolipid antigens that are conservedfeatures of bacterial cell walls. These includeglycosphingolipids from the soil bacterium,Sphingomonas sp. (18), and a diacylglycerol de-rived from the pathogenic spirochaete Borre-lia burgdorferi (19). The NKT cells may alsohave the potential to respond to the bacterialcell wall components derived from the intesti-nal bacteria, and this could account not only

for their abundance in the liver, but also fortheir expression of markers of activation (6).Like many other T cells, the NKT cells expressDAP10- and DAP12-associated receptors, andthe NKG2D receptors on these cells are impli-cated in immunopathology in a mouse modelof hepatitis B in which RAE-1 is induced to en-gage these receptors (20).

The significance of innate immunity in thedefense of the liver is evident from the multi-ple adaptations through which pathogens sub-vert it. Thus, HCV RNA interacts with RIG-Ito activate NF-κB and IFN-β secretion; how-ever, HCV also subverts this pathway becauseits NS3/4 protease cleaves the IPS-1 adaptorprotein of RIG-I signaling (21). IRF-3 may alsobe activated through the TLR3 pathway, butHCV NS3/4 also targets this pathway throughthe cleavage of TRIF (22). Strikingly, this

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mechanism of innate immune escape is alsoseen in hepatitis A virus infection, where theprotease 3ABC cleaves IPS-1 (also known asMAVS), again resulting in subversion of NF-κBactivation (23). This convergence supports theargument that the IRF-3 pathway plays a crit-ical role in antiviral immunity in liver. Apartfrom inhibiting innate immune signaling path-ways within the infected cells, HCV targets NKcells though a completely independent mecha-nism. The HCV envelope protein, E2, binds toCD81 on human NK cells, and this results insuppression of their cytotoxic function and ofIFN-γ synthesis (24). An important feature ofHCV is therefore both a concerted attack onIFN-β synthesis and a major cellular source ofIFN-γ. Because the pathogen so actively sub-verts IFN delivery and function, it is reasonableto suppose that IFN-responsive genes play a keyrole in anti-HCV immunity. It is not, there-fore, surprising that the mainstay of treatmentis high-dose exogenous IFN-α.

Complex protozoan pathogens also manip-ulate the phagocytic function of Kupffer cells.Thus, the malaria parasites Plasmodium sp. en-ter Kupffer cells as part of the process by whichthey cross liver endothelium and gain access tohepatocytes. Evidence in favor of the mecha-nism comes from direct visualization of malariasporozoite behavior in vivo (25) and fromthe observation that parasitization of the liveris reduced in osteopetrotic mice, which lackmature macrophages (26). As part of their in-teraction, the malaria sporozoites disable theKupffer cells’ respiratory burst by increasingintracellular cyclin AMP (27). This effect ismediated by an abundant malaria protein, thecircumsporite protein (CSP), which binds toa Kupffer cell’s surface receptor, LRP-1 (thelow-density lipoprotein receptor-related pro-tein). Thus, the most likely model is thatthe malaria sporozoite’s CSP engages LRP-1,inducing cyclic AMP and suppressing the Kupf-fer cell’s normal response to phagocytosedpathogens. This converts the Kupffer cells fromeffective elements in innate host defense intoportals through which the parasite traverses theendothelium (28).

WORLD PREVALENCE OF LIVER DISEASE

Malaria causes severe disease in 500 million people each year;many more are infected, and 40% of the world population is atrisk. There is no effective vaccine.

More than 350 million people have chronic infection withHBV, which results in one million deaths per year from cirrhosisand liver cancer. A recombinant subunit vaccine is effective, sothis total will probably decline. Around 180 million people areinfected with HCV, and, of these, 130 million are chronicallyinfected and at risk for cirrhosis and liver cancer. There is noeffective vaccine.

sporozoite: thedevelopmental stage ofthe malaria parasitethat infects liver cells

THE DIVERSITY OF POTENTIALANTIGEN-PRESENTING CELLS

The liver contains plasmacytoid DCs (pDCs)and myeloid DCs (mDCs), and pDCs are moreabundant than they are in lymphoid tissue.These pDCs are a major source of IFN-α, con-sistent with the importance of innate immunemechanisms in the liver. But in addition, themouse liver contains two other identifiable sub-sets of DCs, the CD8α+ DCs (29) and theless well-defined natural killer DCs (NKDCs)(30), neither of which has yet been identi-fied in humans. In addition to synthesizingIFN-α, pDCs synthesize both IL-10 and IL-12.In LPS-treated mice, liver pDCs synthesizedless IL-12 than did splenic pDCs (31) and werepoor APCs compared with splenic DCs (32).Conversely, liver mDCs synthesized IL-10, andthis was increased in HCV patients (33). As dis-cussed below, diverse other potential APCs inthe liver respond to TLR ligation by secretingIL-10.

The liver contains a large macrophage pop-ulation; these are the Kupffer cells. In additionto their role as phagocytes, these cells expressMHC and costimulatory molecules, render-ing them potential APCs (Figure 3). However,relatively little work has addressed the APCfunction of Kupffer cells. Early experimentssuggested that Kupffer cells were primarily im-munosuppressive. Thus, addition of Kupffercells to a mixed leukocyte reaction performedin the presence of low arginine resulted in


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TLR4

IL-12/18

IL-10

PD-L1

LPSProteins

Particulates

TNF-α

IFN-γ

KC

HSC

LSECLSEC

T cell

NK cell

Figure 3Immunology of Kupffer cells. These cells can take up LPS, proteins, andparticulates from the blood and secrete a number of cytokines, includingTNF-α, IL-12, and IL-18, but also IL-10. The balance between IL-12/-18 andIL-10 production regulates NK cell activity. Kupffer cells express PD-L1 andhave the capacity to inactivate T cells, a function shared with other liver APCs.Both T cells and NK cells secrete IFN-γ, which powerfully activates Kupffercells. (Abbreviations: KC, Kupffer cell; HSC, hepatic stellate cell.)

LSEC: liversinusoidal endothelialcell

stellate cell: adistinctive liver celltype, located betweenthe liver endothelialcells and thehepatocytes

immunosuppression, mediated in part by PGE2(34). Kupffer cells may also mediate suppressionthrough their synthesis of nitric oxide (35) andrespond to TLR4 ligation by secreting IL-10(36). In a liver transplant model, Kupffer cellsexpressed FasL, leading to alloreactive CD4+ Tcell apoptosis (37). On the basis of such experi-ments, investigators have invoked Kupffer cellsto explain such diverse phenomena as oral tol-erance, portal vein tolerance, and liver allografttolerance. However, Kupffer cells may also actas effective APCs. In HCV infection, humanKupffer cells became MHC I and II high, ex-pressed CD40 and CD80, and formed clusterswith CD4+ T cells, consistent with their actingas APCs (38). Perhaps the capacity of Kupffercells to stimulate or inhibit T cell activation de-pends on the signals to which these cells havebeen exposed. In a study of liver NK cell ac-tivation by human Kupffer cells, the selective

activation of either the TRIF pathway or theMyD88 pathway of TLR signaling resulted inthe predominant expression of either IL-18 orIL-10, leading to higher or lower levels of NKcell activation (39).

The liver sinusoidal endothelial cells(LSECs) have been implicated in antigen pre-sentation (Figure 4). These endothelial cellsare unusual in several respects: They do not se-crete an organized basement membrane, andthey are perforated by numerous fenestrations,clustered into sieve plates. These cells expressthe scavenger receptor, which renders themcompetent to take up circulating proteins. Theyalso express MHC class I and class II and cos-timulatory molecules including CD40, CD80,and CD86, giving them the surface character-istics of highly active stimulatory APCs, suchas DCs (40). However, they respond to TLR4ligation with the secretion of IL-10, to whichthey also respond by downregulating their APCfunctions (41), and their main effect seems to bethe induction of T cell tolerance. Thus, whenLSECs were isolated from mice that receivedovalbumin parenterally or orally, they engagedT cells, resulting in immune deviation to aCD4+ T regulatory phenotype, or in CD8+

T cell tolerance (42, 43).Hepatic stellate cells reside in the suben-

dothelial space of Disse and constitute the pri-mary site for the storage of vitamin A. They reg-ulate hepatic sinusoidal blood flow and can alsotransdifferentiate into myofibroblasts duringthe process of liver fibrosis (44). Recent stud-ies suggest that these cells also belong amongthe liver APCs (Figure 5). Thus, they expressMHC class I, MHC class II, and CD1d, andthey have the potential to respond to innate im-mune signals though their expression of TLR4,CD14, and MD2, which renders them LPSresponsive (45, 46). Ex vivo, stellate cells canactivate NKT cells and classical T cells (47),although their coexpression of the inhibitorymolecule PD-L1 also renders them capable ofT cell inactivation, leading to tolerance (48).

With so many potential liver cell sub-sets manifesting APC activity ex vivo, the is-sue of cell purification becomes particularly

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acute. Classical experiments by Steinman andcolleagues (49) demonstrated that, amongspleen cells, the most powerful APC activitywas concentrated in a very rare subset of cells,the DCs; indeed, the alleged APC activity ofother subsets of spleen cells, including splenicmacrophages, could have been attributed torare, contaminating DCs. This same concernapplies to studies that document the APC ac-tion of ex vivo liver cell subsets, but now we havemore complexity. Which of the APC functionsof a culture of stellate cells may be attributedto rare, contaminating DCs or LSECs? And inthe case of the LSECs, how many contaminat-ing DCs or Kupffer cells is enough to accountfor their ability to activate or to silence a T cellresponse? The optimum reagents for the analy-sis of the significance of APC function would bea series of transgenic mice in which moleculesof interest, such as MHC class I or MHC classII molecules, are expressed or selectively inac-tivated under the control of promoters of ab-solute cell-type specificity. These ideal toolsare not yet at hand; nevertheless, we can drawsome solid conclusions from the extant in vivoexperiments.

LOCAL PRIMING OF T CELLSIN THE LIVER

The presence in the liver of so many distinctsubsets of cells with APC function raises thequestion of whether T cells are in fact activatedlocally in vivo. The distinctive architecture ofthe hepatic sinusoids permits circulating T cellsto make direct contact with underlying hepato-cytes and also with stellate cells, as well as withLSECs and intravascular Kupffer cells. Such in-teractions have in fact been revealed by electronmicroscopy (50), providing a structural basis forprimary T cell activation by hepatocellular anti-gens. This idea was first supported by experi-ments in which CD8+ T cells made a rapid,antigen-driven, local, intrahepatic immune re-sponse in transgenic mice expressing the HBVgenome in both liver and other tissues (51)and subsequently in transgenic mice expressingnonself MHC class I molecules (52). In addi-

TLR4

IL-10LPSProteins

Scavenger-RMannose-R

Transcytosis?

TNF-αCD95L

ICAM-1

MHC I/IICD40/80/86

VCAM-1 VAP-1

Trapping,Tregs,tolerance

LSECLSEC

T

HSC

Figure 4Immunology of liver sinusoidal endothelial cells (LSECs). These cells respondto LPS via TLR4 and can acquire circulating proteins via the scavengerreceptor and the mannose receptor. LSECs may transport proteins acrossthemselves, and into hepatocytes, a process termed transcytosis. They processand present antigens in association with costimulatory ligands (CD40, CD80,and CD86) but respond to ambient LPS by secreting IL-10, biasing T cellstoward tolerance. These cells also express multiple adhesion molecules,including ICAM-1 (intercellular adhesion molecule-1), VCAM-1 (vascular celladhesion molecule-1), and VAP-1 (vascular adhesion protein-1), all of whichare implicated in T cell retention in the liver sinusoids. Thus, these cells canpromote immune tolerance, both through the local trapping of activatedT cells and the induction of regulatory T cells. This concept is summarized inthe diagram as “trapping, Tregs, tolerance.”

tion to transgenic antigens, CD8+ T cells madea local response to antigen delivered specificallyto hepatocytes using an AAV-2 vector, and thisresulted in the subsequent seeding of activatedcells to the lymph nodes and the spleen (53).Furthermore, the transplanted mouse liver, de-pleted of bone marrow–derived APCs, was fullycompetent to activate naive CD8+ T cells inresponse to a peptide antigen (54). Abundantevidence therefore supports the concept thatthe liver is a secondary lymphoid organ, actingas a site of primary T cell activation.

In such experiments, it is not always clearwhich cell population is the main APC. Themost compelling evidence that hepatocytes


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T

NKT

TLR4

LPSTGF-β1

CD1d

HSC

LSECLSEC

KC

IL-10

Figure 5Immunology of hepatic stellate cells. Stellate cells perceive LPS via TLR4 andalso respond to multiple cytokines, including IL-10 and TGF-β1. They expressa high surface density of the nonclassical MHC class I–like molecule CD1d andthereby activate NKT cells.

parenchymal cell:the most abundant celltype in the liver, alsoknown as hepatocytes

cross-presentation:transfer of an antigenfrom the antigen-expressing cell to adistinct APC, resultingin T cell engagement

(also termed liver parenchymal cells) them-selves act as primary APCs comes fromparallel studies in vivo and in vitro, using al-logeneic MHC antigens. In liver allograft ex-periments, cytotoxic T cells underwent sponta-neous apoptosis in the transplanted liver (55),and both hepatocytes and nonparenchymal cellsactivated, then caused apoptosis of, the acti-vated T cells in vitro (56). Similarly, both ac-tivation and apoptosis of T cells were observedin vivo following the adoptive transfer of al-loreactive T cells to transgenic mice expressinga nonself MHC class I molecule on hepatocytes(52, 57). Furthermore, the T cell apoptosis wasalso manifest in vitro when T cells were cul-tured with hepatocytes, leading to the hypoth-esis that a feature of liver tolerance was “deathby neglect,” the engagement of T cells by APCsdeficient in costimulatory activity (58).

In these experiments, the lack of suscep-tibility to cross-presentation of intact MHCmolecules was key in the interpretation of thedata and strongly suggested that hepatocytes

themselves were engaging the CD8+ T cells.However, it is also noteworthy that in all thesestudies the final outcome was T cell inactivationor apoptosis. In a distinct transgenic model, thedeliberate priming of antigen-specific T cellsat an extrahepatic site was not enough to breaktolerance to a transgenic liver antigen expressedin hepatocytes, supporting the argument for anactive state of antigen-driven local tolerance(59).

The presentation of cell-intrinsic MHCantigens by hepatocytes constitutes direct pre-sentation. Similarly, the in vitro analysis ofthe APC functions of stellate cells dealt pri-marily with direct presentation of cellularantigens, or the presentation of exogenouspeptides (47). In vivo experiments revealed thecapacity of stellate cells to act as immunosup-pressive APCs, protecting pancreatic islet al-lografts against rejection (60). In this capacity,also, stellate cells were presenting their intrin-sic antigens. In contrast, we know that LSECsare capable of presenting exogenous antigensencountered in vivo. This is the case for sol-uble antigens given parenterally or orally (42,43). The LSECs also appear to be capable oftrue cross-presentation, in which tumor cell–derived antigen was acquired by LSECs andresulted in CD8+ T cell tolerance (61). Themechanism of this kind of tolerance is likelyto involve PD-L1, based on antibody blockingexperiments (48); in addition, LSECs deficientin this molecule failed to induce CD8+ T celltolerance (62).

In addition to all these nonclassical APCs,DCs also traffic through the liver. Thus, clas-sical mDC precursors expressing CD11c, butnot B220, are recruited to the liver duringgranulomatous inflammation initiated by Pro-pionibacterium acnes and subsequently detectedfirst in the Disse space, then in granulomas,and subsequently in lymphoid aggregates in theportal tracts (63). These movements were or-chestrated by chemokines, with CCL3 drivingthe initial localization to the granulomas, andCCL21 causing the subsequent relocalizationto portal-associated lymphoid tissue (PALT)(64). This certainly suggests, though it does not

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prove, that DCs localize to areas of lympho-neogenesis in the inflamed liver and engage Tcells there. In humans, the same chemokine,CCL21, is expressed by vascular endothelium inportal areas of the liver, but not in lymph nodevessels (65). On this basis, investigators arguethat PALT is a distinct immunological compart-ment; sadly, the acronym lacks distinctivenessbecause it has been applied to lymphoid tissuein the human prostate (66) and in the chickenpineal gland (67). But the existence of PALT,in the hepatic context, adds to the complexityof liver immunology. In addition to examiningdiverse APCs resident in the sinusoids, we alsoneed to consider more conventional lymphoidtissue threaded through the liver in the networkof portal tracts.

THE RISE AND FALL OFLIVER-PRIMED T CELLS

Whereas the immune system is competent toeliminate infection with hepatitis A virus, a stateof persistent infection is a common outcomein HBV infection and the usual outcome inHCV infection. We may therefore ask why liverimmune responses frequently fail. Does thissimply indicate the sophistication of severalwell-adapted pathogens, or, in some sense, isthe liver to blame?

In the case of chronic HCV infection,antigen-specific CD8+ T cells frequently as-sume a stunned or exhausted phenotype, inwhich they express a low level of the IL-7receptor-α (CD127) and a high level of the in-hibitory receptor PD-1 (68). In several infec-tions, including HIV and HCV in humans andlymphocytic choriomeningitis virus in mice,CD8+ T cells with this phenotype are ableneither to secrete IFN-γ nor to make IL-2(69–71). In the case of HCV, another strikingfeature of chronic infection is selective IL-10production by CD4+ T cells (72). Furthermore,chronic HCV in humans may be associated withvery weak or absent CD4+ T cell responses(73), whereas in chimpanzees, viral escape mu-tants that prevent CD4+ T cell recognition fa-

vor chronicity (74), suggesting that the CD8+

T cells may be incapacitated owing to the lackof CD4+ T cell help, a state termed “helpless”(75). To what extent, then, are stunning, exhaus-tion, PD-1 expression, IL-10 intoxication, andhelplessness all effects of the liver environment?

As far as PD-1/PD-L1 interactions are con-cerned, the liver seems to be a preferential siteof action. PD-L1 is expressed on several livercell types (76). Mice deficient in PD-L1 devel-oped an immunoinflammatory hepatitis causedby CD8+ T cells, suggesting a key role forPD-L1 in regulating both CD8+ T cell abun-dance and immunopathology in the liver (77).The immunosuppressive effects of IL-10 se-creted by LSECs, Kupffer cells, and liver pDCshave already been emphasized, along with theinterpretation that this is an effect of low-levelTLR4 ligation. Why should this bias exist? Onepossibility is that the LPS-responsive cells ofthe liver are manifesting a mechanism that hasevolved to suppress chronic immune inflam-mation. Thus, in an acute immune response,IL-10 synthesis occurs after the peak of proin-flammatory cytokines and may help to restorethe system to a resting state. Under conditionsof chronic activation, this mechanism predom-inates, limiting tissue injury. In the liver, thecontinuous presence of low levels of LPS mayemulate chronic inflammation, calling forthIL-10 as a regulatory response.

Does the liver promote CD8+ T cellhelplessness? The liver’s unique vasculaturepermits circulating T cells to engage withhepatocytes (50), which act as APCs (56, 78).Therefore, we can consider the liver as a tissuethat favors CD8+ T cell priming on cells thatcan neither prime nor be engaged by CD4+ Tcells. The helpless phenotype would naturallyfollow from direct priming of HCV-specificand possibly also HBV-specific CD8+ T cellson hepatocytes. In fact, there is one reportof apparently directly primed CD8+ T cellsin the context of liver transplantation. A liverexpressing HLA-A2 was transplanted into anHLA-A2-negative recipient, who subsequentlydeveloped HLA-A2-restricted anti-HCV


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CD8+ T cells (79). This would be consistentwith direct priming on newly infected donorhepatocytes. A further test of the inadequacyof liver-primed CD8+ T cells comes from acomparison of the response of TCR-transgenicT cells to a neo-self-MHC antigen expressedeither exclusively in the liver or also in lymphnodes. Extrahepatic priming resulted infully differentiated CD8+ T cells that couldlocalize to the liver and cause autoimmuneimmunopathology. In contrast, the exclusivelyliver-primed CD8+ T cells were relativelyinnocuous (80).

In summary, multiple mechanisms accountfor the rise and fall of T cells specific for liverpathogens, but many of these effects are linkedto the liver’s unique immunobiology. This is aclear case of contributory negligence; HBV andHCV are subtle and devious pathogens, to besure, but the liver offers them opportunities forimmune subversion.

TGF-β1

PD-L1IL-10

HSC

LSECLSEC

KCT

TTrapping,

FasL,TRAIL,

phagocytosis

Figure 6Mechanisms of T cell tolerance in liver. The expression of adhesion moleculesfacilitates the trapping of activated T cells in liver sinusoids, where they mayundergo apoptosis owing to FasL and TRAIL expressed on Kupffer cells andmay also be phagocytosed. In addition, T cells that recognize antigen in theliver are exposed to immunosuppressive cytokines, including IL-10 andTGF-β1, and to inhibitory ligands, including PD-L1 (also known as B7-H1).

HOW DOES THE LIVER INDUCESYSTEMIC TOLERANCE?

In view of the bias toward tolerance when Tcells encounter antigens in the liver (summa-rized in Figure 6), it is not surprising that sucha large organ can impose systemic immune tol-erance. This phenomenon was first recognizedin the context of allogeneic liver transplanta-tion. In the classic experiments conducted atthe University of Oxford, renal transplants be-tween unrelated pigs were promptly rejected,whereas liver transplants between equally un-related pigs were generally accepted. Strikingly,the transplantation of a kidney and a liver fromthe same donor enhanced the survival of thekidney. In the half-century since the descrip-tion of these “Strange English Pigs”1 (3, 81),this phenomenon has not been fully explained.Many explanations have been considered. Forexample, serial transplantation experiments im-plicated passenger leukocytes as playing a rolein the induction of kidney allograft rejectionand suggested that their loss plays a role inthe induction of allograft tolerance (82). How-ever, the loss of passenger leukocytes cannotbe implicated in the tolerance associated withliver transplantation because of the abundanceof long-lived donor hematopoietic cells withinthe liver graft (83). It was therefore reasonableto propose that, unlike other passenger leuko-cytes, those originating in the liver were tolero-genic. Investigators (84, 85) suggested that thedetection of a low frequency of graft-derivedleukocytes in multiple tissues of a liver trans-plant recipient (microchimerism) explains livertransplantation tolerance, but the survival ofthese cells would be equally well explained ifthe liver were imposing allospecific toleranceby some other mechanism.

If recirculating passenger leukocytes were aneffect rather than a cause of liver allograft tol-erance, what other mechanisms would be can-didates? The sessile Kupffer cells, LSECs, and

1“Strange English Pigs” was the title of an anonymous edi-torial in The Lancet, November 1, 1969, on the topic of liverallograft tolerance.

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stellate cells all have the capacity to present anti-gens to T cells, along with cosignals includingIL-10 and PD-L1 that induce tolerance. There-fore, we may conjecture that liver allograft tol-erance is induced by this mechanism, with per-sistent microchimerism as a by-product. In thismodel, allospecific precursor T cells would en-ter the transplanted liver, undergo activationby liver-specific APCs, and then either undergoparalysis or deletion owing to liver-specific lo-cal signals. We might consider how this mecha-nism could account for the effect of the liver inoral tolerance. The delivery of a protein anti-gen, usually ovalbumin, into the stomach re-sults in systemic tolerance, particularly of Th1CD4+ T cells and CD8+ T cells. If the ve-nous drainage of the gut is surgically diverted,this oral tolerance is lost (86). In the contextof an oral tolerance model, isolated and ex vivocultured LSECs interacted with ova-specific Tcells, activating them but then causing them todeviate their immune function toward an anti-inflammatory pattern of cytokine synthesis (43).While the caveats already raised in relation tothe absolute purity of cultured liver APCs cer-tainly apply to these experiments, they makea prima facie case for the induction of systemictolerance by liver APCs. Similarly, systemic im-mune tolerance can be induced by the injectionof APCs into the portal vein (87), although it isunclear whether these APCs take up residencein the liver and become tolerogenic or whethercross-presentation by resident liver APCsaccounts for this effect.

The induction of systemic tolerance by liverAPCs has been attributed both to peripheraldeletion and to the induction of antigen-specificTregs. Supporting the deletion model is theabundant evidence that activated, circulatingCD8+ T cells are sequestered in the liver, evenin the absence of antigen. This is most strikinglyillustrated in the context of influenza infection,where both virus RNA and protein are limitedto the respiratory system, but influenza-specificCD8+ T cells are found in the liver, associ-ated with Kupffer cell–rich inflammatory fociand with subclinical hepatocyte damage (88).This sequestration depends on integrin lig-

Treg: regulatoryT cell

ands, including ICAM-1 (intercellular adhesionmolecule-1) and VCAM-1 (vascular cell adhe-sion molecule-1) (89), and, like other aspects ofliver tolerance, it may be driven by LPS actingvia TLR4 (90). The evidence that this form ofantigen-independent CD8+ T cell sequestra-tion results in systemic tolerance is thin; how-ever, in the context of a CD8+ T cell responseto antigen-pulsed DCs, the interruption of theTLR4-dependent element of T cell trapping inthe liver resulted in exaggerated systemic im-mune responses, followed eight weeks later byan enhanced secondary response. On the basisof this experiment, John et al. (91) proposed themodel that the liver regulates the magnitude ofCD8+ T cells responses. However, it is abun-dantly clear that deletion is not the fate of everyT cell that enters the liver because liver-derivedT cells can repopulate systemic memory (92).It has been argued that this observation inval-idates the model that the liver acts as a sinkfor activated CD8+ T cells (93), but this argu-ment fails to take into account the distinctionbetween activated blast T cells and CD8+ mem-ory T cells. The data are best reconciled by amodel in which recently activated lymphoblastspreferentially localize to hepatic sinusoids ow-ing to adhesion molecules expressed on LSECs,and then recruit and are killed by Kupffercells, creating a “sink” for excess T cell blasts.Resting memory cells, in contrast, may be over-represented in the liver owing to their adhe-sion receptors, but they do not activate Kupf-fer cells nor are they phagocytosed. These cellsfind the liver quite hospitable, as we have arguedpreviously (94).

The alternative to a deletion model is theidea of active regulation by suppressor T cells,also known as Tregs. These cells exist in avariety of subsets, some of which arise asTregs in the thymus, whereas others differ-entiate from apparently uncommitted periph-eral CD4+ and CD8+ T cell precursors. Theimpact of liver transplantation on these cellsis controversial. A perfusate of human liverwas enriched in CD4+25+FoxP3+CD127low

cells, and such donor-derived Tregs werefound in the circulation of liver transplant


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recipients, an aspect of the phenomenon ofmicrochimerism (95). Investigators agree that,after liver transplantation in humans, theoverall frequency of Tregs in the circulationfalls (96, 97). Among subsets of CD4+25+

T cells, the number of cells that expressedhigh amounts of CD127 increased in humanliver transplant recipients with stable allografts,whereas the number of CD4+25+127low cellswith regulatory function decreased (98); thisis hard to reconcile with the idea that theCD127low regulatory subset was maintainingtolerance. However, in mouse liver transplan-tation, CD4+25+FoxP3+CTLA4+ Tregs in-creased in abundance after liver grafting, anddepletion of these cells using an anti-CD25 an-tibody caused acute rejection of the graft, con-sistent with an important role for these kindsof Tregs in maintaining liver allograft toler-ance and also, by extrapolation, systemic tol-erance (99). It does not follow that mouse andhuman are fundamentally different. The moststraightforward resolution of the apparent con-flict between mouse and human data is thatspontaneous liver allograft acceptance involvesCD4+25+FoxP3+ Tregs but that, in human,liver allografts are tolerated because of im-munosuppression and despite the depletion ofTregs by immunosuppressive drugs.

THE LIVER AS A LYMPHOIDORGAN: CONCLUSIONS

The liver is an important site for primary T cellactivation, but this takes place in an environ-ment biased toward tolerance. Several mech-

anisms contribute to this suppressive milieu.First, the constitutive exposure of liver cells totraces of endotoxin and other microbial prod-ucts results in the down-modulation of costim-ulatory molecules and the synthesis of IL-10by Kupffer cells and LSECs. Second, the openarchitecture of the liver endothelium results inready access of naive T cells to diverse subsetsof APCs, including hepatocytes. This may re-sult in selective CD8+ T cell priming withoutconcomitant CD4+ T cell activation, resultingin a “helpless” phenotype that leads to long-term CD8+ T cell dysfunction and a lack ofimmune memory. Third, the liver endotheliumexpresses adhesion molecules that facilitate thesequestration of circulating activated T cells,particularly CD8+ T cells. This gives the livera role in systemic immunoregulation. An im-portant epiphenomenon resulting from thesemechanisms is liver allograft tolerance.

Because of the high threshold for the initia-tion of an adaptive T cell response in the liver,innate immune mechanisms assume greater sig-nificance. Abundant NK cells and NKT cellsmay be activated by pathogen-associated struc-tures via TLRs, invariant TCRs, or alterna-tive sensing systems such as RIG-I, and bycytokines. Kupffer cells respond to inflamma-tory cytokines such as IFN-γ by the synthesisof their own inflammatory mediators: TNF-α,IL-12, and IL-18. These in turn deliver posi-tive signals to both adaptive and innate immunecells. Awash with potential activating signals,the liver’s immune system is held in a baselinestate of active tolerance, which can be reversedby sufficiently strong pathogen-specific signals.

SUMMARY POINTS

1. The liver receives blood from the intestine, which is rich in microbial products. Theseengage TLRs, which modify innate immunity in the hepatic environment.

2. The liver lymphocytes are enriched in CD8+ T cells, activated T cells, memory T cells,NKT cells, and NK cells.

3. Multiple cell populations can act as APCs in the liver. These include hepatocytes, en-dothelial cells, and subendothelial stellate cells, as well as several subsets of dendriticcells.

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4. The liver is rich in immunosuppressive cytokines including IL-10, and several liver cellsubsets express the inhibitory ligand PD-L1. The consequence of this is that many en-counters between T cells and liver APCs end in immune tolerance.

FUTURE ISSUES

1. The mechanisms of antigen presentation and T cell activation by the many subsets ofliver APCs must be clarified. In particular, do these cell types form distinctive synapseswith T cells? Which of them engage in cross-presentation of hepatocellular antigens?What mechanisms promote such cross-presentation?

2. In hepatitis B, hepatitis C, hepatocellular cancer, and the liver stage of malaria, how arehepatocellular antigens presented to the immune system?

3. Which immune mechanisms favor the elimination of hepatocellular antigens? Whichmechanisms cause liver immunopathology? How can we promote the former, whilelimiting the effects of the latter?

DISCLOSURE STATEMENT

The author is not aware of any affiliations, memberships, funding, or financial holdings that mightbe perceived as affecting the objectivity of this review.

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AR371-FM ARI 16 February 2009 15:37

Annual Review ofImmunology

Volume 27, 2009Contents

FrontispieceMarc Feldmann � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � x

Translating Molecular Insights in Autoimmunity into EffectiveTherapyMarc Feldmann � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �1

Structural Biology of Shared Cytokine ReceptorsXinquan Wang, Patrick Lupardus, Sherry L. LaPorte,and K. Christopher Garcia � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 29

Immunity to Respiratory VirusesJacob E. Kohlmeier and David L. Woodland � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 61

Immune Therapy for CancerMichael Dougan and Glenn Dranoff � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 83

Microglial Physiology: Unique Stimuli, Specialized ResponsesRichard M. Ransohoff and V. Hugh Perry � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �119

The Liver as a Lymphoid OrganIan Nicholas Crispe � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �147

Immune and Inflammatory Mechanisms of AtherosclerosisElena Galkina and Klaus Ley � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �165

Primary B Cell Immunodeficiencies: Comparisons and ContrastsMary Ellen Conley, A. Kerry Dobbs, Dana M. Farmer, Sebnem Kilic,Kenneth Paris, Sofia Grigoriadou, Elaine Coustan-Smith, Vanessa Howard,and Dario Campana � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �199

The Inflammasomes: Guardians of the BodyFabio Martinon, Annick Mayor, and Jürg Tschopp � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �229

Human Marginal Zone B CellsJean-Claude Weill, Sandra Weller, and Claude-Agnes Reynaud � � � � � � � � � � � � � � � � � � � � � �267

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AR371-FM ARI 16 February 2009 15:37

AireDiane Mathis and Christophe Benoist � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �287

Regulatory Lymphocytes and Intestinal InflammationAna Izcue, Janine L. Coombes, and Fiona Powrie � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �313

The Ins and Outs of Leukocyte Integrin SignalingClare L. Abram and Clifford A. Lowell � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �339

Recent Advances in the Genetics of Autoimmune DiseasePeter K. Gregersen and Lina M. Olsson � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �363

Cell-Mediated Immune Responses in TuberculosisAndrea M. Cooper � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �393

Enhancing Immunity Through AutophagyChristian Munz � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �423

Alternative Activation of Macrophages: An Immunologic FunctionalPerspectiveFernando O. Martinez, Laura Helming, and Siamon Gordon � � � � � � � � � � � � � � � � � � � � � � � �451

IL-17 and Th17 CellsThomas Korn, Estelle Bettelli, Mohamed Oukka, and Vijay K. Kuchroo � � � � � � � � � � � � � �485

Immunological and Inflammatory Functions of the Interleukin-1FamilyCharles A. Dinarello � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �519

Regulatory T Cells in the Control of Host-Microorganism InteractionsYasmine Belkaid and Kristin Tarbell � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �551

T Cell ActivationJennifer E. Smith-Garvin, Gary A. Koretzky, and Martha S. Jordan � � � � � � � � � � � � � � �591

Horror Autoinflammaticus: The Molecular Pathophysiology ofAutoinflammatory DiseaseSeth L. Masters, Anna Simon, Ivona Aksentijevich, and Daniel L. Kastner � � � � � � � � �621

Blood Monocytes: Development, Heterogeneity, and Relationshipwith Dendritic CellsCedric Auffray, Michael H. Sieweke, and Frederic Geissmann � � � � � � � � � � � � � � � � � � � � � � � �669

Regulation and Function of NF-κB Transcription Factors in theImmune SystemSivakumar Vallabhapurapu and Michael Karin � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �693

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Education

The liver as a lymphoid organ annu rev