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Antigen-presenting cell function in the
tolerogenic liver environment
Angus W. Thomson* and Percy A. Knolle‡
Abstract | The demands that are imposed on the liver as a result of its function as a metabolic
organ that extracts nutrients and clears gut-derived microbial products from the blood are
met by a unique microanatomical and immunological environment. The inherent
tolerogenicity of the liver and its role in the regulation of innate and adaptive immunity are
mediated by parenchymal and non-parenchymal antigen-presenting cells (APCs),
cell-autonomous molecular pathways and locally produced factors. Here, we review the
central role of liver APCs in the regulation of hepatic immune function and also consider how
recent insights may be applied in strategies to target liver tolerance for disease therapy.
Oral tolerance
The immunological mechanism
whereby the mucosal immune
system maintains
unresponsiveness to antigens
in the mucosal environment
that might otherwise induce
undesired immune responses.
Portal venous tolerance
The induction of peripheral
tolerance following portal
venous delivery of antigen
(most commonly alloantigen).
Reticulo-endothelial system
The general phagocytic system
of the host. It is responsible for
the removal and destruction of
foreign material and senescent
or dead host cells, such as red
blood cells.
*Starzl Transplantation
Institute, Department of
Surgery, and the Department
of Immunology, University of
Pittsburgh School of Medicine,
Pittsburgh, Pennsylvania
15261, USA.
‡
Institutes of Molecular
Medicine and Experimental
Immunology, University
Hospital Bonn, 53105 Bonn,
Germany.
e-mails:
[email protected];
[email protected]
doi:10.1038/nri2858
The liver is located at a crossroads of the systemic
circulation, between blood that reaches the liver
through the hepatic artery and blood that enters the
liver through the portal vein containing gut-derived nutrient-rich blood. Arterial and venous blood mix in the liver,
resulting in low oxygen tension, low perfusion pressure
and slow and irregular blood flow within the thin-walled
hepatic microvessels, which are known as sinusoids. The
strategic position of the liver in the blood circulation
allows it to carry out its metabolic functions in lipid, carbohydrate and protein generation and in the degradation
of toxic or waste products (FIG. 1a). Anatomically, the liver
comprises repetitive functional units that are defined by
the vascular supply structures, giving rise to a meshwork
of sinusoidal vessels that supply the metabolic units, the
hepatocytes, with blood (FIG. 1b). Hepatocytes are separated from the bloodstream by non-parenchymal liver
cells: a thin layer of fenestrated liver sinusoidal endothelial
cells (LSECs) that are devoid of a basement membrane and
stellate cells, which are located in the small space of Dissé
between LSECs and hepatocytes. Other non-parenchymal
cell populations in the liver include Kupffer cells, which
are resident and immobile hepatic macrophages that are
located in the sinusoidal lumen (mainly in the periportal
area), dendritic cells (DCs), which are found preferentially
in the periportal and pericentral area, natural killer (NK)
cells and NKT cells, which migrate through the hepatic
sinusoids, and a dispersed but sizeable population of
liver-associated lymphocytes (FIG. 1c).
Unique hepatic regulatory mechanisms prevent the
induction of immunity against innocuous antigens,
such as gut-derived nutrients, antigens from aged or
damaged cells that are cleared from the circulation in
the liver and neo-antigens that arise by adduct formation of metabolic products during detoxification of,
for example, alcohol. Such immune regulation has to
resist stimulation by bacterial degradation products in
the portal venous blood — such as lipopolysaccharide
(LPS) from Gram-negative bacteria in the gut — that
potently stimulate antigen-presenting cells (APCs).
The tolerogenic properties of the liver are exemplified by its roles in oral tolerance and portal venous
tolerance, the persistence of microbial infections and
tumour metastases in the liver, and the comparative
immune privilege of hepatic allografts. As outlined in
more detail below, the initial encounter of naive T cells
with antigen in the liver, rather than in lymphoid tissue, is a key aspect of hepatic adaptive immune tolerance. However, unlike immune privileged sites, such
as the eye, the liver allows innate immunity to eliminate microbial infections. The competing demands
of immunity to pathogens and tolerance to antigens
metabolized in the liver are met by two mechanisms:
the innate immune functions of non-parenchymal
cells that separate hepatocytes from pathogens and the
regulatory immune functions of hepatocytes and nonparenchymal cells that act as local APCs in distinct
anatomical niches.
The liver microenvironment and innate immunity
Kupffer cells, DCs and LSECs constitute the hepatic
reticulo-endothelial system, which clears antigens, degradation products and toxins from sinusoidal blood by uptake
through endocytic receptors (such as mannose receptors
and scavenger receptors) and which can transfer some
of these ligands to hepatocytes for metabolic conversion.
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a
Inferior
vena cava
Portal tract
Liver sinusoidal
circulation
Blood from the
arterial circulation
Liver:
Nutrition, synthesis
and detoxification
Hepatic artery
Glisson’s
capsule
b
To the systemic venous circulation
Metabolic products:
• Protein
• Lipids
• Carbohydrates
Acute phase proteins
Common
bile duct
Portal vein
Blood from the intestines
• Nutrients from the gut
• Bacterial degradation
products
• Aged or damaged cells
• Toxic components
Central vein
To the intestinal lumen
Bile secretion (containing end
products of detoxification)
Bile duct
Arteriole
c
Portal vein
Hepatocyte
Narrow
vessel
diameter
LSEC
PGE2
Slow blood flow
Mixed arteriovenous perfusion
(low oxygen
tension)
Space of Dissé
Microvillus
TGFβ
TGFβ
Kupffer cell
IL-10
IL-10
IL-10
TGFβ
T cell
Stellate cell
PGE2
Arginase
IL-10
Dendritic
cell
Hepatic
sinusoid
TGFβ
Arginase
Figure 1 | metabolic functions of the liver, general anatomy and location of liver APCs and factors that regulate
their function. a | The metabolic functions of the liver and the flow of products through the portal vein, hepatic artery,
inferior vena cava and common bile duct. b | General microanatomy of the liver, showing the location
of central
veins and
Nature Reviews
| Immunology
portal tracts, as well as the direction of blood flow. c | Anatomical location of hepatic antigen-presenting cells (APCs) and
the factors that regulate their function. Branches of the hepatic artery merge with sinusoidal vessels carrying blood from
the portal vein in the liver, resulting in a mixed arterio-venous perfusion of the liver with low oxygen tension. Owing to
extensive branching of portal vessels into liver sinusoids, and the accompanying increase in cumulative vessel diameter,
the hepatic microcirculation is characterized by low pressure and slow, sometimes irregular, blood flow. Together with the
narrow diameter of hepatic sinusoids, this facilitates the interaction of circulating leukocytes with hepatic sinusoidal cell
populations. The hepatic sinusoids are lined by a population of microvascular liver sinusoidal endothelial cells (LSECs) that
separate hepatocytes and stellate cells (all of which function as APCs) from leukocytes circulating through the liver in the
blood. Fenestrations in the LSEC lining allow the passive exchange of molecules between the space of Dissé and the
blood156, as well as direct contact of lymphocyte filopodia with hepatocyte microvilli115. The liver interstitium is highly
enriched in cells of the innate immune system (such as antigen-presenting dendritic cells, Kupffer cells, natural killer (NK)
cells and NKT cells (not shown)) and in T cells, which participate in adaptive immune responses157,158. Mediators produced
by both parenchymal and non-parenchymal cells, including interleukin-10 (IL-10), transforming growth factor-β (TGFβ),
arginase and prostaglandin E2 (PGE2), regulate immune function within the liver.
Transcytosis
The process of transport of
material across a cell layer by
uptake on one side of the cell
into a coated vesicle. The
vesicle might then be sorted
through the trans-Golgi
network and transported to the
opposite side of the cell.
blood-borne pathogens, such as the hepatotropic hepatitis b virus (Hbv) and hepatitis C virus (HCv), as well
as Plasmodium parasites1–3, exploit this endocytic capability as a portal of entry into the liver and apparently
escape cell-autonomous immunity in these scavenger
cells to infect their target cells (hepatocytes) following
transcytosis. Nevertheless, these scavenger cells express
various pattern recognition receptors (Prrs) that allow
them to mount potent innate immune functions. For
example, Kupffer cells express high-affinity Fc receptor
for igA (Fcαri; also known as CD89) and complement
receptor of the immunoglobulin superfamily (Crig;
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Box 1 | Immune cell recruitment to the liver
Pattern recognition receptor
(PRR). A host receptor (such as
Toll-like receptors (TLRs) or
NOD-like receptors (NLRs)) that
can sense pathogen-associated
molecular patterns and initiate
signalling cascades that lead to
an innate immunity. These
receptors can be membrane
bound (such as TLRs) or soluble
cytoplasmic receptors (such as
retinoic acid-inducible gene-I,
melanoma differentiation
associated gene 5 or NLRs).
Glycocalyx
A carbohydrate-rich coating
that covers the outside of
many eukaryotic and
prokaryotic cells, particularly
bacteria, and which, on
bacterial cells, provides a
protective coat from host
factors.
Pathogen-associated
molecular patterns
(PAMPs). Molecular patterns
that are found in pathogens
but not mammalian cells.
Examples include terminally
mannosylated and
polymannosylated compounds,
which bind the mannose
receptor, and various microbial
products, such as bacterial
lipopolysaccharides,
hypomethylated DNA, flagellin
and double-stranded RNA,
which bind to Toll-like receptors.
Acute phase proteins
A group of proteins, including
C-reactive protein, serum
amyloid A, fibrinogen and
α1-acid glycoprotein, that are
secreted into the blood in
increased or decreased
quantities by hepatocytes in
response to trauma,
inflammation or disease. These
proteins can be inhibitors or
mediators of inflammatory
processes.
Indoleamine
2,3-dioxygenase
(IDO). An intracellular
haem-containing enzyme that
catalyses the oxidative
catabolism of tryptophan.
Insufficient availability of
tryptophan can lead to T cell
apoptosis and anergy.
Glisson’s capsule
The capsule of the liver. A layer
of connective tissue that
surrounds the liver and
ensheathes the hepatic artery,
portal vein and bile ducts
within the liver.
Liver-resident cells influence local immunoregulation not only in terms of their antigen-presenting cell (APC) function
but also through the recruitment of leukocyte populations. Circulating immune cells in the liver first make contact
with sinusoidal cells, such as liver sinusoidal endothelial cells (LSECs) or Kupffer cells. Because of the slow blood flow
in hepatic sinusoids143, leukocyte adhesion does not require the expression of selectins by the endothelium144. Under
physiological conditions, MHC class I-restricted antigen presentation by LSECs and hepatocytes leads to
antigen-specific recruitment of naive CD8+ T cells and represents the first step in local tolerance induction145,146.
Circulating dendritic cells (DCs) are recruited by Kupffer cells in a C-type lectin-dependent manner to hepatic
sinusoids147, where they enter the lymphatic circulation or remain liver-resident36, suggesting that there is a
continuous influx of DCs from the blood into the liver. Under conditions of local inflammation, certain adhesion
molecules and distinct sets of chemokine–receptor pairs, which are presented on the endothelial glycocalyx148,
regulate immune cell recruitment — for example, CC-chemokine receptor 6 (CCR6) and CCR9 for cytotoxic T
lymphocytes (CTLs), CXC-chemokine receptor 3 (CXCR3), CCR5 and CXCR6 for T helper 1 (TH1) cells, and CCR4 and
CCR8 for TH2 cells149. Binding to adhesion receptors also confers specificity for cell-specific attraction: TH1 and TH2
cells are recruited independently from each other by vascular cell adhesion molecule 1 (VCAM1; also known as
CD106) and vascular adhesion protein 1 (VAP1), respectively150, whereas CTLs are arrested by binding to intercellular
adhesion molecule 1 (ICAM1) and VCAM1 (REF. 151). Interestingly, hepatic recruitment of regulatory T cells requires
distinct receptors: CXCR3 for LSEC-dependent recruitment and CCR4 for DC-dependent recruitment152. These
examples show that, under tolerizing steady-state conditions, T cell recruitment is antigen specific, whereas immune
cell recruitment under inflammatory conditions depends on antigen nonspecific mechanisms to increase the numbers
of effector or regulatory T cells to either increase or attenuate local immunity. Immune cell attraction to the liver
requires tight control, because aberrant cell recruitment can overcome local tolerogenic mechanisms and trigger the
development of autoimmunity153.
a C3 receptor that enhances complement-mediated
phagocytosis), which promote the efficient removal of
complement-coated blood-borne bacteria4,5, generating a second line of defence against liver infection by
pathogens that breach mucosal immunity in the gut.
Stimulation of Prrs by pathogen-associated molecular patterns (PAmPs) leads to the activation of hepatic scavenger
cells and the expression of pro-inflammatory mediators,
such as interleukin-6 (iL-6). in turn, this triggers hepatocellular expression of acute phase proteins (such as complement and C-reactive protein) that bind to pathogens
and enhance phagocytosis but decreases detrimental
tumour necrosis factor (TNF) release by Kupffer cells6.
Prr activation also induces the expression of adhesion
molecules and chemokines by endothelial cells, leading
to immune cell recruitment to the liver, which modulates
the induction of local tolerance or immunity depending
on the cells that are recruited (BOX 1) — regulatory T
(Treg) cells or effector T cells. Prr activation also triggers
the expression of immunoregulatory molecules, such as
iL-10, transforming growth factor-β (TGFβ) and prostanoids7. Hepatic expression of arginase and indoleamine
2,3-dioxygenase (iDO)8,9 has antimicrobial activity, but it
also impedes local adaptive immunity by the metabolism
of amino acids that are essential for immune cell proliferation. Taken together, the constitutive and functional
expression of Prrs by hepatic cell populations leads to
the induction of innate immunity, allowing local as well
as systemic antimicrobial activity, but also restricts the
local induction of adaptive immunity. Here, we describe
the molecular mechanisms that underlie the tolerogenic
functions of the different types of hepatic APC, how
they may be overcome to mount immunity and how
such insight into liver immunobiology may be applied
in therapeutic strategies to regulate immunity in liverspecific autoimmune and viral diseases, cancer and liver
transplantation.
Liver DCs
Localization, recruitment, differentiation and migration.
The normal mouse liver contains more interstitial
DCs than other parenchymal organs10, which may be a
consequence of the PAmPs contained in portal blood.
DCs in the liver are restricted largely to the perivenular
region, portal space and beneath the Glisson’s capsule,
with a few cells scattered throughout the parenchyma11.
The cytokines FMS-like tyrosine kinase 3 ligand (FLT3L)
and granulocyte–macrophage colony-stimulating factor (Gm-CSF), which mobilize DCs from the bone
marrow, markedly increase the number of liver DCs12.
DCs can also be propagated in vitro from liver nonparenchymal cells13. Under steady-state conditions,
mouse and human liver DCs have tolerogenic properties14–16. The local microenvironment (which can
be mimicked in vitro using liver fibroblastic stromal
cells) seems to be important for programming CD117+
haematopoietic progenitor cells to differentiate into
tolerogenic DCs that suppress T cell proliferation,
induce apoptosis of activated T cells and inhibit experimental autoimmune hepatitis17. by secreting macrophage
colony-stimulating factor and hepatocyte growth factor, liver stromal cells drive haematopoietic progenitor
cells to differentiate into iL-10hiiL-12low regulatory or
tolerogenic DCs18,19 that exert their function through
various mechanisms, including the production of antiinflammatory prostaglandin E2 (PGE2) (which can upregulate iDO expression by DCs or increase iL-10 production)20. After differentiation into DCs by co-culture with
rat liver epithelial cells, human monocytes secrete iL-10
but not iL-12p70 and direct T helper 2 (TH2) cell, rather
than TH1 cell, polarization21, which may favour cytokinedriven immune regulation. Thus, the liver microenvironment influences the induction of tolerogenic DCs.
mechanisms by which DCs and other liver APCs mediate
tolerogenic effects are summarized in TABLE 1.
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Table 1 | Regulatory mechanisms of liver antigen-presenting cells
Cell type
mechanisms
Effect
outcome
Myeloid DCs
Production of PGE2
Inhibition of T cell proliferation; apoptosis of activated T cells
Tolerance
17
Production of IL-10
Generation of TReg cells and TH2 cells through IL-10-dependent
mechanisms; decreased production of TNF, IL-6 and ROS by
monocytes
Tolerance
16,60
Modulation of function by TGFβ
Induction of TReg cells with PD1-dependent regulatory function
Tolerance
46
Secretion of IL-27
Induction of T cell hyporesponsiveness
Tolerance
44
Co-stimulation; IL-12p70 production
T cell activation and/or proliferation
Immunity
163
Increased MHC class II and
co-stimulatory molecule expression
TH1 cell polarization
Immunity
66
IL-10 production; low Delta 4/Jagged1
Notch ligand ratio
Skewing to TH2 cell differentiation; CD4+ T cell apoptosis
Tolerance
52
Expression of B7-H1
Impaired T cell stimulatory function
Tolerance
49
Low level of peptide–MHC complex
and co-stimulatory molecule expression
Induction of anergy or deletion of antigen-specific T cells and
TReg cell function
Tolerance
53,164
High IFNα production
NK, NKT and CD8+ T cell activation
Immunity
47
Production of PGE2 and 15d-PGJ2
Inhibition of antigen-specific T cell activation
Tolerance
79
IL-10 and TGFβ production
Suppression of inflammatory cytokine production
Tolerance
80,81,88
Plasmacytoid DCs
Kupffer cells
LSECs
Hepatocytes
Stellate cells
Refs
Proliferation and programming of TReg cells
Tolerance
82,83
CD1-dependent presentation of
bacterial antigens
Activation of NKT cells
Immunity
91
Expression of B7-H1
B7-H1-mediated T cell tolerance after initial stimulation
Tolerance
98,101
Expression of LSECtin
Inhibition of CTL function
Tolerance
112
Expression of CD95L
CD4 T cell tolerance after transendothelial migration
Tolerance
96
Expression of CD95L
Death of activated T cells
Tolerance
97
Absence of IL-12 production; uncertain
Failure to induce functional TH1 cells but generation of
regulatory T cells
Tolerance
93,154
Inhibition of DC-mediated stimulation
of naive T cells
Veto of CD8+ T cell activation
Tolerance
114
Viral infection causing expression of
undefined co-stimulatory molecules
Full CTL differentiation
Immunity
106
Failure to provide co-stimulation
AICD in naive T cells
Tolerance
116,165
B7-H1 expression
Inhibition of CTL effector function
Tolerance
162
Ectopic expression of autoantigen
Generation and proliferation of TReg cells
Tolerance
141
NKT cell co-activation
Induction of IL-10-producing CD8 T cells
Tolerance
119
Upregulated MHC class II expression
Activation of CD4+ T cells
Immunity
120
Post-vaccination activated CD8+ T cells Activation of naive CD8+ T cells
upregulate hepatocyte MHC class I
expression
Immunity
123
Expression of B7-H1 or TRAIL by
activated stellate cells
Regulation of T cell responses through B7-H1 or
TRAIL-mediated apoptosis
Tolerance
127,128
Retinoic acid and TGFβ independent
Proliferation of TReg cells
Tolerance
129
Antigen presentation to CD1- and
MHC-restricted NKT and T cells
Activation and/or proliferation of T cells and NKT cells
Immunity
126
+
+
15d-PGJ2, 15-deoxy-delta12,14-PGJ2; AICD, activation-induced cell death; CTL, cytotoxic T lymphocyte; DC, dendritic cell; IFNα, interferon-α; IL, interleukin;
L, ligand; LSEC, liver sinusoidal endothelial cell; LSECtin, liver and lymph node sinusoidal endothelial cell C-type lectin; NKT cell, natural killer T cell;
PD1, programmed cell death 1; PGE2, prostaglandin E2; ROS, reactive oxygen species; TGFβ, transforming growth factor-β; TH2 cell, T helper 2 cell;
TNF, tumour necrosis factor; TRAIL, TNF receptor apoptosis-inducing ligand; TReg cell, regulatory T cell.
Several DC subsets are found in mouse liver 22. As in
the spleen, the main populations are conventional myeloid DCs (mDCs) (CD11c+CD8α–CD11b+) and CD8α+
DCs (CD11c+CD8α +CD11b –) 23,24. relative to these
subsets, the incidence of plasmacytoid DCs (pDCs)
(CD11clowb220+LY6C+CD11b–SiGLECH+)25 in the liver is
higher than in secondary lymphoid tissue23. pDCs originate in the bone marrow from myeloid and lymphoid
progenitors26,27 and detect viral rNA or DNA28. in addition to type i interferons (iFNs), pDCs secrete iL-6, iL-12
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Box 2 | Endotoxin tolerance
Intrahepatic scavenger cells, such as dendritic cells (DCs), Kupffer cells and liver
sinusoidal endothelial cells (LSECs), clear pathogen-associated molecular patterns
(PAMPs) from the circulation. Constitutive expression of pattern recognition receptors,
such as Toll-like receptors (TLRs), confers sentinel function to these cells, which are
stimulated by PAMPs and release pro-inflammatory mediators, such as tumour necrosis
factor (TNF). The development of inflammation may be prevented by the concomitant
expression of regulatory mediators (such as interleukin-10 (IL-10) and transforming
growth factor-β (TGFβ)), or by the development of cell-autonomous hypo- or
non-reactivity to subsequent stimuli. This hyporesponsive state towards PAMPs, known
as ‘endotoxin tolerance’, is achieved by negative regulators of TLR signalling (such as
IL-1 receptor activating kinase-M or p50–p50 nuclear factor-κB homodimers), by
soluble immune regulatory molecules (such as IL-10) or even by epigenetic
modifications41. The tolerant state extends to several TLRs (cross-tolerance) and to
sequential encounters of TLRs and endotoxin, as well as to TLRs and ischaemic injury.
Interestingly, the scavenger function of these cell populations is not affected by
endotoxin tolerance – they even have upregulated expression of relevant scavenger
molecules41, thus ensuring continuous clearance of PAMPs from the hepatic circulation
without inducing inflammation. Importantly, liver scavenger cells are not functionally
matured as antigen-presenting cells (APCs) to induce adaptive immunity by such
stimulation with PAMPs, whereas similar treatment of identical cell populations from
other organs promotes strong immunity43,106. This argues for the existence of particular
cell-intrinsic mechanisms within hepatic APCs for maintenance of the tolerogenic
phenotype or, alternatively, high local concentrations of anti-inflammatory mediators
in the liver that inhibit local APC maturation.
FMS-like tyrosine kinase 3
ligand
(FLT3L). An endogenous
cytokine that stimulates the
proliferation of stem and
progenitor cells through
binding to the FLT3 receptor (a
type III receptor tyrosine
kinase member of the
platelet-derived growth factor
family). FLT3L administration
substantially increases the
number of dendritic cells in
lymphoid and non-lymphoid
tissues.
Portal-associated lymphoid
tissue
(PALT). An inducible,
liver-specific immune tissue
that may act as a first line of
defence of the lymphatic
pathway, as well as a site of
local induction of immunity in
the liver.
and TNF. in humans, mDCs (CD11c+CD11b+bDCA1+)
are also the most prominent liver DC subset 29, and
they produce substantial amounts of iL-10, induce
antigen-specific T cell hyporesponsiveness and generate both Treg cells and iL-4-producing TH2 cells through
an iL-10-dependent mechanism16. Detailed studies of
human liver pDCs (CD11c–CD123+bDCA2+bDCA4+)
have not been carried out, although a relatively small
population of pDCs has been identified in human
hepatic lymph nodes30.
immature DCs expressing CC-chemokine receptor 1 (CCr1) and CCr5 are recruited from the circulation to the rat liver in response to CC-chemokine
ligand 3 (CCL3) secreted by Kupffer cells in the sinusoidal area31,32. DCs bind to Kupffer cells through
N-acetylgalactosamine-mediated interactions33. Unlike
other liver APCs, DCs are highly motile and migrate
from the rat liver at a rate of ~10 5 DCs per hour 34.
immunohistochemical staining has been used to show
that particle-laden immature rat DCs with monocyte
morphology (mHC class ii+OX62+) migrate in the liver
from the sinusoidal to the portal or hepatic vein areas,
then translocate to celiac lymph nodes through hepatic
lymphatics34–36. Presumptive hepatic pDCs have not
been found in hepatic or intestinal lymph37. During their
migration, hepatic DCs upregulate CCr7 expression and
responsiveness to CCL19 and CCL21 (REF. 38), thereby
promoting homing to lymphoid tissue that produces
these chemokines31. inflammation can convert liver DCs
from a tolerogenic to an activating phenotype. During
inflammation, DCs in the space of Dissé form close
contacts with lymphocytes and similar interactions are
observed in the portal tracts39. in granulomatous liver
disease, DCs within portal-associated lymphoid tissue
(PALT) seem to activate T cells40.
Tolerogenic properties. The refractory behaviour
of freshly isolated liver mDCs to LPS stimulation is
known as ‘endotoxin tolerance’ 41, a transient hyporesponsiveness to LPS that may extend to other Toll-like
receptor (TLr) ligands (‘cross tolerance’) (BOX 2). FIG. 2
depicts the mechanisms by which this DC unresponsiveness to LPS may be induced and/or maintained in
the liver microenvironment under steady-state conditions. mouse liver-resident bulk DCs or purified mDCs
are less mature, phenotypically and functionally, than
those from secondary lymphoid tissue23,42,43. They
express lower levels of mHC class ii and co-stimulatory
molecules43, secrete less iL-12 after TLr ligation42 and
preferentially produce iL-10 and iL-27 (REF. 44). They
are poor stimulators of naive allogeneic T cells23,42,43 and
of TH1 cell polarization43 but promote TH2 cell skewing 45. In vivo transfer of mouse liver-derived immature
mDCs into naive, untreated allogeneic recipients elicits iL-10-producing T cells45 and prolongs pancreatic
islet allograft survival14. interactions between hepatic
NK cells and hepatocytes in vitro through the inhibitory receptor NKG2A on NK cells prime liver-derived
DCs to induce Treg cells that rely on programmed cell
death 1 (PD1) to inhibit CD4+CD25– effector T cells46.
Such cell–cell interactions may be important for the
promotion of tolerance by liver DCs.
Normal mouse liver pDCs express low levels of mHC
class ii molecules and low or undetectable levels of CD40,
CD80 and CD86, and they are weak T cell stimulators47.
whereas splenic pDCs can present and cross-present antigens to CD4+ and CD8+ T cells48, respectively, albeit less
efficiently than conventional mDCs, liver pDCs fail to do
so47 for reasons that are unclear. Liver pDCs secrete less
iFNα than spleen pDCs after CpG-containing DNA49 or
cytomegalovirus stimulation50, and it seems that, as for
mDCs in the liver, exposure to microbial products can
inhibit liver pDC function. Among the PAmPs that reach
the liver from the gut is the peptidoglycan muramyl dipeptide (mDP), a ligand of nucleotide-binding oligomerization domain 2 (NOD2). NOD2 is a Prr that mediates
resistance to microbial infection and regulates innate
and adaptive immune responses51. NOD2 is expressed
at higher levels by mouse liver or spleen pDCs than by
mDCs49. Following exposure to mDP in vivo, mouse
liver pDCs (but not spleen pDCs) upregulate expression
of iFN regulatory factor 4 (irF4) (FIG. 3), a negative regulator of TLr signalling that competes with irF5 for binding to myeloid differentiation primary response protein 88
(mYD88) and inhibits TNF receptor-associated factor 6
(TrAF6) activation. This results in less allogeneic T cell
proliferation and iFNγ production as a consequence of
increased expression of the co-inhibitory molecule b7-H1
(also known as PDL1) by the liver pDCs. NOD2 ligation
also impairs iL-6, iL-12p70, TNF and iFNα production
by liver pDCs in response to stimulation with TLr4 or
TLr9 ligands49. Thus, exposure to mDP compromises the
stimulatory function of liver pDCs.
There is strong evidence to show that unstimulated
pDCs can induce T cell tolerance. mouse liver pDCs
produce more iL-10 and less bioactive iL-12p70 than
their splenic counterparts52. Furthermore, liver pDCs
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Treg cells. mouse liver pDCs induce efficient CD4+ and
CD8+ T cell tolerance to orally administered antigens
that reach the liver through the blood53. Thus, pDCs in
the liver microenvironment promote in vivo tolerance
by inducing anergy or deletion of circulating T cells.
The ability of liver pDCs to rapidly and efficiently
delete oral antigen-specific T cells is consistent with the
liver being a site for CD4+ (REF. 54) and CD8+ (REF. 55)
T cell apoptosis.
Gut-derived LPS
(through the portal vein)
Hepatic cytokine
production
Liver
IL-6
IL-10
TGFβ
LPS
TLR4
IL-10
DAP12
IRAK-M
IL-10R
STAT3
Cytokine
modulation of
hepatic DCs
↑ IL-10
Liver myeloid DC
P
NF-κB
P
↓IL-12
↑IL-10
IL-6R
SMAD
↓ IL-12
IL-6
CD80
TGFβRII
TGFβRI
↓
CD86
TGFβ
Co-stimulatory
molecule
expression
Figure 2 | mechanisms downmodulating the responsiveness of liver myeloid
dendritic cells to lipopolysaccharide. Recent evidence indicates that gut-derived
commensal bacterial products, typified by lipopolysaccharide
(LPS),
inhibit
mouse
Nature
Reviews
| Immunology
liver dendritic cell (DC) maturation by stimulating production of hepatic
interleukin-6 (IL-6). In turn, this stimulates signal transducer and activator of
transcription 3 (STAT3) activity downstream of the IL-6 receptor (IL-6R) in liver
DCs159. Hepatic DCs in normal, wild-type mice are phenotypically and functionally
less mature than DCs from IL-6-deficient or STAT3-inhibited IL-6-sufficient mice.
Moreover, IL-6-induced STAT3 signalling seems to increase the expression of IL-1
receptor-activating kinase M (IRAK-M), a negative regulator of Toll-like receptor
(TLR) signalling (that would otherwise lead to DC maturation), in liver CD11c+ DCs.
IL-10 and transforming growth factor-β (TGFβ), which are produced by various liver
cell populations, signal through STAT3 and SMAD proteins, respectively, to repress
activation of nuclear factor-κB (NF-κB), thus inhibiting hepatic DC maturation. In
addition, there is new evidence that the transmembrane adaptor protein
DNAX-activating protein of 12 kDa (DAP12), which has been implicated in the
negative regulation of TLR responses in DCs160, is expressed at comparatively high
levels by liver myeloid DCs and negatively regulates their maturation in association
with IRAK-M expression161. This results in impaired production of the T helper 1 (TH1)
cell-inducing cytokine IL-12, but increased secretion of IL-10.
express a low Delta4/Jagged1 Notch ligand ratio and
thus skew towards TH2 cell differentiation and promote allogeneic CD4+ T cell apoptosis (FIG. 3). T cell
proliferation in response to liver pDCs is enhanced by
blocking iL-10. in the absence of Treg cells, liver pDCs
are equally efficient inducers of T cell proliferation as
spleen pDCs52, suggesting that, under steady-state conditions, the inferior T cell stimulatory ability of liver
pDCs may depend on the presence and function of
Role in liver injury and disease. Ischaemia–reperfusion
injury occurs after organ procurement from donors
and organ preservation following reperfusion in vivo.
Hepatic ischaemia–reperfusion injury increases systemic
and portal endotoxaemia, leading to TLr4-dependent
enhanced activation of transcription factors, such
as nuclear factor-κb (NF-κb) and activator protein 1
(AP1), that cause increased iL-6 and TNF expression
in the liver 56,57. The use of chimeric mice with inactive
TLr4 on hepatocytes, but wild-type TLr4 on bone
marrow-derived cells, including DCs, has indicated
that TLr4 activity on leukocytes is necessary for liver
ischaemia–reperfusion injury 58. However, there are conflicting reports regarding the role of liver DCs. On the
one hand, there is evidence that during liver ischaemia–
reperfusion injury, DCs may be protective because they
express increased iL-10 and TGFβ and decreased levels of iL-12p40 (REF. 59). indeed, targeted depletion of
mouse mDCs under steady-state conditions increases
liver ischaemia–reperfusion injury 60. Hepatocyte DNA
released from damaged cells has been identified as an
endogenous ligand of TLr9 that promotes mDCs to
secrete iL-10 (REF. 60), which decreases the production
of iL-6, TNF and reactive oxygen species (rOS). On the
other hand, a Gm-CSF-induced increase in liver DC
numbers can exacerbate ischaemia–reperfusion injury
through release of the endogenous danger-associated
molecular pattern (DAmP) high-motility group box 1
(HmGb1)61, which increases responsiveness of hepatic
DCs to TLr4 stimulation61 and interacts with receptor
for advanced glycation end products (rAGE) and TLr9
(REF. 62) to activate DCs. Although these discrepancies
may relate to differences between the models used,
further study is required to clarify the role of DCs in
hepatic injury.
Liver allografts have inherent tolerogenicity 63 that
has been associated with the persistence of donor
DC progenitors with tolerogenic properties in host
lymphoid tissue64. However, if FLT3L is administered
to donors before liver transplantation to increase the
number of potentially stimulatory liver DCs 47,65,66,
acute allograft rejection occurs in mice that otherwise
accept liver grafts without immunosuppression12. This
may be explained by the finding that both mDCs12 and
pDCs47 from FLT3L-mobilized livers have increased
expression of CD80, CD86 and mHC class ii molecules and enhanced allogeneic T cell stimulatory
capacity compared with normal liver DCs. The rejection of FLT3L-treated donor livers may thus result
from the enhanced TH1 cell-polarizing ability of the
liver DCs after FLT3L mobilization66. Thus, inhibiting
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LPS
Microbial stimuli
TLR4
MHC class IIlow
↓ T cell proliferation
and IFNγ production
T cell
Liver
pDC
CD40low
MDP
CpG DNA
PD1
NOD2
CD80low
B7-H1
TLR9
Endosome
CD86low
IRF4
↓ Pro-inflammatory
cytokines
IL-6
IL-12
TNF
↓ Type I IFN
↓ Delta4/Jagged1 ratio
↑ IL-10
Notch
Notch ligand
↑ T cell apoptosis
↑ TH2 cells
↑ TReg cells
Figure 3 | Functional biology of liver plasmacytoid DCs. Unlike conventional
myeloid dendritic cells (DCs), plasmacytoid DCs (pDCs) are characterized by their
Naturestimuli
Reviews
| Immunology
ability to secrete type I interferons (IFNs) in response to microbial
that
ligate
Toll-like receptors (TLRs) (such as CpG-containing DNA or lipopolysaccharide (LPS)) or
nucleotide-binding oligomerization domain (NOD) receptors (such as muramyl
dipeptide (MDP)). In vivo exposure of liver pDCs to the NOD2 ligand MDP upregulates
expression of IFN regulatory factor 4 (IRF4), a negative regulator of TLR signalling, and
impairs the ability of pDCs to secrete pro-inflammatory cytokines in response to TLR
ligands and their capacity to induce T cell proliferation and IFNα production. These
MDP-stimulated liver pDCs have increased cell surface B7-H1 expression, the absence
of which (for example, on B7-H1-deficient liver pDCs) reverses the inhibitory effect of
MDP on liver pDC function. The ability of liver pDCs to rapidly delete oral
antigen-specific T cells is consistent with the liver as a site of CD4+ and CD8+ T cell
apoptosis. The mechanisms by which liver pDCs may regulate T cell responses include
the expression of B7-H1, modulation of Notch ligand expression (which promotes
T helper 2 (TH2) cell differentiation), production of interleukin-10 (IL-10) (which
promotes regulatory T (TReg) cell differentiation) and T cell apoptosis. PD1, programmed
cell death 1; TNF, tumour necrosis factor.
Ischaemia–reperfusion
injury
Cellular damage caused by the
return of a blood supply to a
tissue after a period of
inadequate blood supply. The
absence of oxygen and
nutrients causes cellular
damage such that restoration
of the blood flow results in
inflammation.
the TH1 cell-polarizing cytokine iL-12 in recipients of
these livers suppresses graft rejection67. rejection of
FLT3L-treated donor livers may also reflect a breach
of endotoxin tolerance. Although hepatic DCs from
FLT3L-treated donors have characteristics of endotoxin
tolerance, such as decreased iL-12 secretion after LPS
or CpG-containing DNA42 stimulation that results from
their exposure to PAmPs in the liver, they may be more
susceptible to reversal of the tolerant state68 and thus
able to act as stimulators of host effector T cells.
in hepatocellular carcinoma, the tumours lack
immunogenic CD83+ DCs69, which might aid tumour
immune escape. by contrast, higher proportions of
all intrahepatic DC subsets have been associated with
decreased viral load in Hbv infection70. mDCs from
HCv-infected livers express increased levels of CD86,
CD123 and mHC class ii molecules, are more efficient
stimulators of allogeneic T cells and secrete less iL-10
than mDCs from non-infected, inflamed liver 71. pDCs
are also abundant in HCv-infected livers72, but their role
in the innate control of infection is uncertain; they are
not infected directly or stimulated by the virus. HCvinfected hepatocyte cell lines can initiate a strong type i
iFN response in pDCs that requires active viral replication, direct cell–cell contact and TLr7 signalling, which
results in inhibition of HCv infection73. However, despite
this defence mechanism involving pDCs, HCv infection
is rarely overcome.
Taken together, these data show that liver DC subsets are crucially involved in the regulation of innate and
adaptive immunity. Their expression of Prrs and molecular regulators of immunity (cytokines, prostaglandins
and cell surface co-regulatory molecules), their responses
to microbial products and locally produced mediators
and their interactions with other liver leukocyte populations and T cells in secondary lymphoid tissue influence
the balance between tolerance and immunity.
Kupffer cells
Kupffer cells are the largest population of tissueresident macrophages. in mice, CD68+ (macrosialin)
and CD11b+ subsets of F4/80+ Kupffer cells with phagocytic and cytokine-producing ability, respectively, have
recently been described74. Kupffer cells are ideally situated in the hepatic sinusoids to encounter circulating
T cells, as well as NK and NKT cells. They have been
reported in the portal tract and in hepatic lymph nodes
a few days after selective loading with phagocytic markers75. Their importance as tolerogenic APCs has been
shown in the induction of tolerance to soluble antigens76,
and in portal venous77 and liver transplant tolerance78.
Similarly to DCs, mouse steady-state Kupffer cells
express low levels of mHC class ii and co-stimulatory
molecules and can inhibit DC-induced antigen-specific
T cell activation through the production of PGE2 and
15-deoxy-delta12,14-PGJ2 (15d-PGJ2)79. Although these
findings ruled out a role for iL-10, nitric oxide, iDO,
TGFβ and amino acid starvation in Kupffer cell-induced
T cell suppression under steady-state conditions, LPSactivated Kupffer cells are a major source of both iL-10
(the production of which is subject to negative autoregulation)80 and TGFβ81. Under steady-state conditions,
Kupffer cells can stimulate the suppressive activity of
Treg cells. interaction between Kupffer cells and Treg cells
induces iL-10 expression by Treg cells, which is crucial for
the induction of tolerance to hepatocyte-expressed antigens82. This suppressive function can be overcome in the
presence of TLr ligands, when Kupffer cells can override
Treg cell-mediated suppression and promote T cell proliferation83. High-affinity peptide (SiiNFEKL) presentation by Kupffer cells leads to the initial proliferation of
activated cytotoxic TCr-transgenic (OT-i) CD8+ T cells
administered through the portal vein, but it causes their
intrahepatic deletion through apoptosis84, thus inhibiting cytotoxic T lymphocyte (CTL)-mediated immunity locally in the liver. Kupffer cells are responsible for
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Danger-associated
molecular pattern
(DAMP). As a result of cellular
stress, cellular damage and
non-physiological cell death,
DAMPs are released from the
degraded stroma (for example,
hyaluronate), from the nucleus
(for example, high-mobility
group box 1 protein (HMGB1))
and from the cytoplasm (for
example, adenosine
triphosphate, uric acid, S100
calcium-binding proteins and
heat-shock proteins). Such
DAMPs are thought to elicit
local inflammatory reactions.
recruitment of CTLs to the liver during viral infection of
the lung 85, which at first seems to be contradictory, but
may be explained indirectly by Kupffer cell-dependent
recruitment of bone marrow-derived APCs to the liver.
The innate function of Kupffer cells has a role in liver
injury through the production of pro-inflammatory
cytokines, complement activation and rOS production86,
as their elimination ameliorates liver ischaemia–reperfusion injury 87. As with liver DCs, however, conflicting
findings have been reported. For example, recent data
indicate that, through iL-10 expression, Kupffer cells
may protect mouse livers subjected to hepatic warm
ischaemia–reperfusion injury with bowel congestion
(mimicking clinical liver transplantation) by regulation
of the inflammatory response88.
Kupffer cells are the dominant hepatic APCs that
present lipid antigens in a CD1-restricted manner to
NKT cells in the liver, as depletion of DCs does not influence hepatic NKT cell stimulation89. by contrast, DCs are
required to activate splenic NKT cells through CD1, indicating that there are organ-specific differences in NKT cell
stimulation89. These differences may be related to: the
relative paucity of DCs in the liver compared with the
spleen; the distinct hepatic microarchitecture that does
not enforce DC–NKT cell interaction; or undefined cellintrinsic mechanisms in hepatic DCs regulating antigen
presentation by CD1. However, the generation of additional iFNγ-dependent TH1 cell responses in response
to lipid antigens in the liver strictly depends on feedback
signalling between DCs and NKT cells, leading to iL-12
expression by DCs that, in turn, stimulates iFNγ release
Box 3 | Intrahepatic regulatory T cells
In comparison to the spleen, the liver contains relatively few CD4+CD25+FOXP3+
regulatory T (TReg) cells, although various hepatic antigen-presenting cells (APCs)
support TReg cell development — for example, antigen presentation by hepatocytes
induces antigen-specific regulatory T cells that prevent the development of
autoimmune disease even in extrahepatic sites, such as the central nervous system141.
Both natural killer (NK) cell-primed mouse liver myeloid dendritic cells (mDCs)46 and
freshly isolated human liver mDCs16 induce the differentiation of regulatory T cells, and
the poor T cell stimulatory activity of liver plasmacytoid DCs (pDCs) is associated with
TReg cell function52. Liver sinusoidal endothelial cells (LSECs) also induce the
differentiation of regulatory T cells154, which protect from autoimmune hepatitis by
suppressing T helper (TH) cell-dependent immunity154. The molecular mechanisms of
such regulatory T cell induction by LSECs have not been defined in detail, but are
different from those used by tolerogenic DCs, because LSEC-dependent regulatory
T cells express low levels of CD25 and are forkhead box P3 (FOXP3)– regulatory T cells.
Whereas functional plasticity for development into certain TH cell populations has been
observed for TReg cells under certain conditions, the regulatory function of
LSEC-induced FOXP3– regulatory T cells is maintained under inflammatory
conditions154, assuring continuous control of local immunity.
There may be implications for the low abundance of liver TReg cells: first, this may
allow a rapid switch from tolerance to immunity once tolerogenic antigen presentation
by liver-resident APCs is overcome and, second, the various tolerogenic mechanisms
operating in the liver may already be sufficient to control unwanted immune responses
and do not support TReg cell recruitment, which depends on inflammation-derived
signals154,155. These explanations are not mutually exclusive. However, upon induction
of immune responses that trigger APC activation and local inflammation, various
hepatic cells, such as hepatocytes, DCs, LSECs and stellate cells, rapidly expand
liver-resident TReg cells or recruit circulating TReg cells. Such an increase in TReg cell
numbers under these conditions may prevent immunopathology, but may also
promote the development of persistent hepatic infections.
from NK cells89. Nevertheless, Kupffer cells are important
local stimulatory APCs during hepatic infections when
PAmPs drive their activation: they cross-present parasite
antigens in Leishmania donovani-induced granulomas to
CD8+ T cells90 and present Borrelia burgdorferi-derived
lipid antigens on CD1 to NKT cells91. in both situations,
Kupffer cells support the development of antimicrobial
immunity, suggesting that, in the infectious microenvironment, they help to mount intravascular immunity.
However, the ability of Kupffer cells to induce T cellmediated immunity could also lead to liver damage in the
absence of hepatic infection. For example, the uptake and
presentation by Kupffer cells of systemically circulating
antigens from pathogens, such as influenza virus infecting the lung, leads to local activation of influenza-specific
CD8+ T cells in the liver, which eventually results in collateral liver damage85. This may provide an explanation
for the bystander hepatitis that is often observed during
systemic viral infection.
Taken together, these findings show that Kupffer
cells support tolerance induction towards circulating
and hepatocyte-derived antigens, whereas encounter
of antigen in the context of microbial infection leads to
strong intravascular immunity. Apparently, interaction
with other immune cell populations, such as NKT cells
or CTLs, is required to develop the full potential of
Kupffer cells to mediate antimicrobial immunity 92.
Liver sinusoidal endothelial cells
LSECs line the hepatic sinusoids and are unique microvascular endothelial cells that resemble lymphatic
endothelial cells and repopulate from liver-derived progenitor cells. LSECs are efficient scavenger cells, and they
sample circulating and hepatocyte-derived antigens for
processing and presentation on mHC class i or mHC
class ii molecules. As a result of this APC function,
LSECs help to locally shape the immune function of
T cells at different levels.
mouse LSECs express only low levels of mHC class ii
molecules and do not express iL-12, even after TLr
stimulation, which accounts for their failure to function
as professional APCs to induce TH cell differentiation93.
They present soluble antigens to CD4+ T cells94, a function
that is controlled by endotoxin, which decreases antigen
processing, providing evidence for microenvironmental
control of liver APC function95. LSECs prime naive
CD4+ T cells93, although high antigen concentrations are
required for this. in contrast to priming by DCs, priming of naive CD4+ T cells by antigen-presenting LSECs
does not promote TH cell differentiation, but neither does
it lead to clonal elimination of such T cells93. instead,
LSECs induce the development of forkhead box P3
(FOXP3)– Treg cells (BOX 3).
by contrast, in the setting of liver transplantation,
donor-derived LSECs may directly control the function
of alloreactive T cells. by virtue of their APC function,
liver-resident LSECs can present antigens directly from
phagocytosed allogeneic cells. This results in T cell elimination by CD95 ligand (CD95L; also known as FASL)dependent apoptosis or contact-dependent inhibition of
proliferation and effector function of surviving T cells
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that transmigrate across LSECs96,97 — mechanisms that
may contribute to the tolerogenic function of liver transplants63. At present, the molecular mechanisms determining these distinct outcomes of antigen presentation to
CD4+ T cells by LSECs are unclear, but they may be related
to context-dependent changes during organ transplantation that result in local inflammation and cell death. Taken
together, the data show that LSECs skew T cell responses
by inhibiting TH cell differentiation, through the induction of regulatory T cells or by elimination or inhibition
of effector CD4+ T cells.
Similarly to professional APCs, mouse LSECs crosspresent exogenous antigens to CD8+ T cells98. whereas
cross-presentation of ovalbumin by DCs relies on mannose
receptor-mediated antigen uptake99, LSECs use various
endocytic receptors, such as the mannose and scavenger
receptors, to sample ovalbumin for cross-presentation,
Naive
CD8+ T cell
Tolerization
PD1
TCR
B7-H1
MHC
class I
Transmigrating
CTL
DC
Inhibition of
CTL function
Apoptosis
LSEC
Space
of Dissé
Stellate cell
Unknown ligand
B7-H1
Hepatocyte
Figure 4 | Different hepatic antigen-presenting cells use B7-H1 to promote local
T cell tolerance. Antigen presentation by liver sinusoidal endothelial
cells| Immunology
(LSECs) to
Nature Reviews
naive CD8+ T cells leads to their specific recruitment from the blood and causes
upregulation of B7-H1 and programmed cell death 1 (PD1) by LSECs and T cells,
respectively, achieving tolerogenic maturation of both cell populations98,101,146.
Naive CD8+ T cells do not transmigrate from the blood because T cell receptor
(TCR)-triggering by antigen-presenting LSECs provides a migration stop signal146.
After initial expansion and contraction of T cell populations, B7-H1-mediated T cell
tolerance is characterized by lack of effector cytokine expression and cytotoxic
activity101. Hepatic dendritic cells (DCs) may also promote T cell tolerance, depending
on B7-H1 expression49. After transmigration across sinusoidal cells into the space of
Dissé, activated cytotoxic T lymphocytes (CTLs) encounter stellate cells that induce
T cell apoptosis through B7-H1 (REF. 127). However, the pro-apoptotic effect of B7-H1
on stellate cells is not mediated by PD1 but by an as yet undefined ligand on T cells127.
B7-H1 on hepatocytes has distinct effects on naive CD8+ T cells versus activated CTLs:
high B7-H1 levels on antigen-presenting hepatocytes increase priming of naive T cells
(not shown), whereas B7-H1 expression inhibits release of effector cytokines and
cytotoxic activity by CTLs162. These findings reveal distinct functions of B7-H1 on the
various hepatic APCs: B7-H1 expression on hepatic DCs and LSECs located in the
hepatic sinusoids provides a front-line defence system that skews the immune
response towards induction of tolerance in circulating naive T cells. By contrast,
B7-H1 expression on stellate cells and hepatocytes attenuates the effector functions
of liver-infiltrating CTLs that have crossed the sinusoidal cell layer.
and they are more potent in terms of cross-presentation
than splenic DCs100. LSECs phagocytose material of up
to 200 nm in size, whereas Kupffer cells are most effective at the phagocytosis of larger complexes, giving rise
to a division of labour between LSECs and Kupffer cells
in the clearance of particulate antigens from the circulation for cross-presentation to CD8+ T cells. After initial
stimulation of naive CD8+ T cells by LSECs, expression of
activation markers by T cells and T cell proliferation are
observed, but eventually LSECs induce the development
of tolerance in naive CD8+ T cells, which is characterized
by the failure to develop cytotoxic effector function and
the absence of effector cytokine expression98. Tolerance
induction in CD8+ T cells does not entail clonal deletion
but depends on the interaction between co-inhibitory
b7-H1 molecules on LSECs and PD1 molecules on CD8+
T cells101 (FIG. 4) — a mechanism that contributes to oral
tolerance, as well as to tolerance towards apoptotic cell
material that is eliminated in the liver 102,103. The induction of tolerance is preceded by the mutual upregulation of b7-H1 and PD1 expression on the respective cell
populations, resulting from cognate interactions between
mHC class i molecules and TCrs, which shows that tolerance induction is an active process. Tolerogenic programming of T cells by LSECs depends on the balanced
delivery of stimulatory and inhibitory signals, as increasing co-stimulatory signalling through CD28 overcomes
tolerogenic b7-H1–PD1 signalling 101. Likewise, increasing signal strength through the TCr also breaks tolerance induction through the production of iL-2 by T cells
as an autocrine co-stimulatory factor that is dominant
over b7-H1-mediated signalling 104. During viral infection, LSECs take up more hepatotropic viruses (such as
hepadnaviruses and HCv) from the blood than do other
hepatic cells1,105. Presentation of viral antigens may result
in the induction of virus-specific T cell tolerance and viral
immune escape, which can eventually promote persistent
viral infection of the liver.
in contrast to DCs in lymphoid tissue, which become
functionally mature and immunogenic after activation
through Prrs, LSECs (similarly to hepatic DCs) do not
mature after stimulation through TLrs or through the
cytoplasmic helicase Prrs retinoic acid-inducible gene i
or melanoma differentiation-associated gene 5 (REF. 106),
which have been implicated in viral double-stranded
rNA recognition. This might be a mechanism to promote tolerance induction in the liver, despite the presence of gut-derived microbial PAmPs in portal venous
blood107. Although stimulation of DCs108 or Kupffer
cells91 by NKT cells leads to their functional maturation, the importance of such interactions for the immune
function of LSECs is unclear. Taken together, the data
identify LSECs as liver APCs that skew the local immune
response towards the induction of T cell tolerance and
resist functional maturation in response to PAmPs.
LSECs also have immunoregulatory functions that
are independent of their APC properties. various C-type
lectins, such as DC-specific intracellular adhesion molecule-3-grabbing non integrin (DC-SiGN; also known as
CLEC4L), liver and lymph node (L)-SiGN (also known
as CLEC4m) and liver and lymph node sinusoidal
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endothelial cell C-type lectin (LSECtin; also known as
CLEC4G), are expressed by human LSECs109,110. These
molecules facilitate interactions with T cells, but also
shape T cell immune functions111. For example, LSECtin
interacts with CD44 on activated, but not resting, T cells
and leads to inhibition of T cell proliferation, induction of
T cell apoptosis and downregulation of the expression of
effector cytokines, such as iL-2 and iFNγ113. Absence of
LSECtin aggravates murine autoimmune liver disease112,
as does the absence of the co-inhibitory molecule b7-H1
(REF. 113), showing that the control of T cell effector function by LSECs contributes to the prevention of immunemediated liver damage. in addition to direct regulation
of effector T cells, LSECs negatively regulate the APC
function of DCs. Direct physical contact with LSECs
causes DCs to lose the ability to prime naive T cells, and
may thereby inhibit immunogenic T cell priming in the
liver 114. Thus, the antigen nonspecific regulation of T cell
and APC function by LSECs probably provides a local
threshold to ‘fine tune’ the extent of immune effector
functions in the liver.
However, T cell tolerance induction by LSECs is
overcome during viral infection. Triggering of Prrs
by microbial PAmPs in portal venous blood fails to
functionally mature LSECs, whereas viral infection of
these cells promotes the development of CD8+ T cell
immunity 106. Such induction of effector T cells by virusinfected LSECs is independent of the well-known costimulatory molecules CD80 and CD86 and overrides
tolerogenic b7-H1 signalling, suggesting that local T cell
immunity is controlled by new co-stimulatory mechanisms that operate specifically in the liver and still need
to be defined106. The rapid local induction of T cell
immunity in the liver during infection may be advantageous to the host to quickly control infection, as it does
not require the time-consuming steps of APC migration
to lymphatic tissue, CTL proliferation and recirculation
to the infected site. Taken together, the data show that
LSECs are versatile non-migratory APCs that, on the one
hand, are equipped with unique mechanisms to resist
functional maturation in response to PAmPs and maintain their contribution to the hepatic tolerogenic phenotype but, on the other hand, promote the local induction
of T cell immunity during microbial infection.
Hepatocytes
The metabolic functions of the liver are carried out
mainly by hepatocytes. As these metabolic processes can
lead to the emergence of neoantigens — for example,
by adduct formation during detoxification — hepatocyte-mediated antigen presentation to CD4+ and CD8+
T cells may trigger autoimmune responses. Hepatocytes
can contact circulating lymphocytes directly through
endothelial fenestrations in mouse liver that allow contact between hepatocyte microvilli and T cell filopodia115.
Although mouse hepatocytes express relatively low levels
of mHC class i molecules, they can prime naive CD8+
T cells owing to their large cell size116. However, although
naive T cells primed by antigen-presenting hepatocytes
undergo initial clonal expansion, they are eventually clonally eliminated owing to a lack of sufficient co-stimulation
followed by bCL-2-interacting mediator of cell death
(bim)- and caspase-dependent apoptosis117, identifying
pro-apoptotic bim as a crucial initiator of T cell death in
the liver. Consequently, the first contact of naive CD8+
T cells with their cognate antigen on hepatocytes leads
to immune tolerance by clonal deletion, whereas the first
encounter with antigen on professional APCs in lymphoid
tissue triggers CTL differentiation and the development
of CTL-dependent autoimmune hepatitis in mice upon
re-encounter with antigen on hepatocytes118. moreover,
CD1-restricted interaction of hepatocytes with canonical NKT cells leads to the generation of iL-10-expressing
CD8+ T cells with regulatory function119.
Under pro-inflammatory conditions, mouse hepatocytes express mHC class ii molecules and function
as APCs for CD4+ T cells120. Such antigen presentation
generates defective TH cell responses, characterized by the
preferential induction of TH2 cells from naive CD4+ T cells
and prevention of iFNγ release from already committed
TH1 cells, which synergistically impairs CD8+ T cellmediated antiviral immunity 121. This TH cell skewing by
mouse hepatocytes may be related to low expression levels
of Delta-like Notch ligands that are key promoters of TH1
cell differentiation and stimulation122. in addition, hepatocytes generate Treg cells that actively contribute to hepatic
tolerance (BOX 3). However, most results on the tolerogenic
APC function of hepatocytes have been obtained from
transgenic overexpression of mHC class i or mHC class
ii molecules, the expression of which is low under physiological conditions. However, given the large number of
hepatocytes in the liver, it is possible that expression of
mHC class i and ii molecules, even on a small percentage
of cells, may be sufficient to trigger immune tolerance.
Hepatocytes can also support the induction of
T cell immunity under certain situations. Following
vaccination, recently activated CD8+ T cells enter
the mouse liver and, by still undefined mechanisms,
induce increased mHC class i expression in combination with CD80 and CD86 expression by hepatocytes,
which causes a switch from tolerogenic to immunogenic
antigen presentation123. Also, following infection with
adeno-associated virus (AAv), which preferentially
infects hepatocytes, local antigen presentation leads to
induction of T cell immunity and the clearance of infection, indicating that the tolerogenic effect of hepatocytes alone may be insufficient to explain the chronicity
of viral infection in the liver 124. Although these studies
do not reveal the mechanisms by which changes in the
local environment overcome tolerance induction, they
suggest that hepatocytes function mainly as tolerogenic
APCs under steady-state conditions.
Hepatic stellate cells
Following their activation during inflammation, stellate
cells differentiate into myofibroblasts for the production of extracellular matrix, leading to hepatic fibrosis.
in culture, they carry out endocytosis and phagocytosis
and express mHC class i and ii molecules, lipid-presenting molecules (CD1b and CD1c) and T cell costimulatory molecules, such as CD86, the expression of
which on human stellate cells is markedly upregulated
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by pro-inflammatory cytokines125. mouse stellate cells
cross-prime CD8+ T cells, present lipid antigens to liver
NKT cells and promote their homeostatic proliferation through the production of iL-15 (REF. 126). Despite
constitutive expression of b7-H1, stellate cells are not
tolerogenic APCs but rather contribute to the induction
of antimicrobial immunity 126 for reasons that are not
defined. However, there is evidence that activated mouse
stellate cells restrict adaptive immunity through b7-H1or TNF receptor apoptosis-inducing ligand (TrAiL)mediated T cell apoptosis127,128 and the iL-2-dependent
clonal expansion of Treg cells129. These mechanisms may
allow stellate cells to prolong pancreatic islet allograft
survival130. The contribution of stellate cells to hepatic
immunity or tolerance needs to be better defined. it
is unknown whether liver fibrosis, which is associated
with stellate cell activation and their transformation into
fibroblasts, modifies their immune function.
Targeting liver tolerance for disease therapy
The concept of active induction of tolerance by APCs
located in the hepatic sinusoids implies that the intravascular compartment of the liver is an anatomical structure
that supports the deliberate induction of tolerance. Here,
the sinusoidal APCs — LSECs, Kupffer cells and liver
DCs — present antigen in a tolerogenic manner to naive
T cells, thereby skewing the immune response towards
tolerance for hepatocyte-derived as well as circulating
antigens. LSECs and Kupffer cells, as ‘authentic’ liver-resident APCs, trigger tolerance locally, whereas liver DCs
may also promote immune tolerance in lymphoid tissue.
Effector T cells that succeed in crossing the sinusoidal
barrier are likely to be functionally inhibited or clonally
eliminated upon recognition of antigen on LSECs, stellate cells and even hepatocytes. Potentially, this inherent
tolerogenicity of the liver could be exploited to suppress
undesired immune responses.
Clinical trials using AAv-mediated gene transfer
into hepatocytes for the correction of haematological
disorders, such as haemophilia, have yielded promising
results131; however, pre-existing AAv-specific memory
T cells restricted long-term transgene expression in
transduced hepatocytes132,133. As experimental studies in
animals devoid of such memory T cells showed prolonged
expression of viral transgenes in the liver 134, it is reasonable
to assume that liver-intrinsic tolerance mechanisms might
be used to increase the duration of hepatocellular transgene expression provided that pre-existing memory T cell
responses are controlled. interestingly, hepatic Treg cells
seem to be required for prolonged transgene expression
in hepatocytes in a non-human primate model135. New
delivery methods (for example, the use of functionalized
nanocapsules targeting LSECs for therapeutic transgene
expression in animal models of haemophilia A136) can
circumvent the problem of pre-existing memory T cell
responses to the viral vector that cannot be influenced by
tolerogenic antigen presentation in the liver.
improved acceptance of liver transplants may also
be achieved using liver-inherent tolerogenic mechanisms; clinical trials in which pharmacological immunosuppression is gradually reduced and even withdrawn137
may allow the development of immune tolerance138
through an active process, as described above. more specifically, the tolerogenicity of liver DCs may be increased
by the delivery of non-toxic TLr agonists139 and/or downregulators of TLr signalling or by the adoptive transfer of
ex vivo-expanded and peptide-loaded liver DCs (as shown
for model antigens140) in order to achieve immune tolerance towards specific autoantigens that cause autoimmune
hepatitis. The observation that liver-induced tolerance
controls autoimmunity in the central nervous system141
raises hope that extrahepatic autoimmune diseases could
also be targeted using this approach.
with respect to breaking liver tolerance to allow
the clearance of persistent infection or cancer treatment, overcoming the tolerogenic properties of hepatic
APCs may improve intravascular immunity, but this
approach needs adequate experimental testing. it is
unclear whether reversing the tolerogenic function of
liver APCs alone will be sufficient to allow the development of strong hepatic immunity. A key question
may be the feasibility of Treg cell depletion in a liverspecific manner. As persistent infections and cancer are
located within the hepatic parenchyma, the tolerogenic
hepatic environment that fails to support effector T cell
responses would need to be controlled, or T cells would
need to be rendered resistant to these inhibitory effects,
to improve intrahepatic effector T cell functions.
Concluding remarks
Since the initial account of the liver as a tolerogenic organ
more than 40 years ago63, we have accumulated extensive
knowledge, largely from rodent studies, of the molecular
and cellular mechanisms responsible for local hepatic
skewing of immune responses. more human studies
are needed, as the relevance of much of this work for
immune regulation in human liver is largely unknown.
Liver tolerance influences both local and extrahepatic
immune reactivity, showing that the principles governing local hepatic immune regulation have far-reaching
consequences for our understanding of systemic immune
regulation. whereas the concept ‘form follows function’
has been used to describe the development of particular anatomical compartments that allow optimal execution of distinct immune responses in lymphoid tissue142,
immune function in the liver is better characterized
by ‘function follows form’, whereby parenchymal and
non-parenchymal cells have dual functions — metabolic and immunological — in the context of a unique
microanatomy. Hepatic sinusoidal APCs, such as DCs,
Kupffer cells and LSECs, delicately balance intravascular
immune responses in the liver, suggesting that the huge
cumulative surface area of the hepatic sinusoids functions as an immunoregulatory platform aimed at skewing
immune responses in steady-state conditions, as well as
during exposure to blood-borne pathogens. Liver parenchymal tissue should be considered a unique anatomical
compartment, characterized by distinct mechanisms of
tolerance induction focused on the restriction of effector
T cell function. This knowledge provides the basis for the
development of new immune therapies that enhance or
break local immunoregulatory circuits in the liver.
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Acknowledgements
The authors’ work is currently supported by US National
Institutes of Health grant P01 AI81678 and the Roche Organ
Transplantation Research Foundation (874,279,717) (to
A.W.T.) and by DFG grants SFB 704, SFB TR57, GRK 804
and SFB 670 (to P.A.K.).
Competing interests statement
The authors declare no competing financial interests.
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