Originally published online as doi:10.1189/jlb.0107062 on April 30, 2007
Published online before print April 30, 2007
(Journal of Leukocyte Biology. 2007;82:457-464.)
© 2007
by Society for Leukocyte Biology
Lymphocyte function during hepatic ischemia/reperfusion injury
Charles C. Caldwell,
Johannes Tschoep and
Alex B. Lentsch1
The Laboratory of Trauma, Sepsis and Inflammation Research, Department of Surgery, University of Cincinnati, Cincinnati, Ohio, USA
1 Correspondence: University of Cincinnati College of Medicine, Department of Surgery, 231 Albert Sabin Way, Cincinnati, OH 45267-0558, USA. E-mail: alex.lentsch{at}uc.edu
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ABSTRACT
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The liver is the primary organ affected by ischemia/reperfusion (I/R) injury after shock, surgical resection, or transplantation. The actions of myeloid leukocytes have been well studied and are thought to be the primary cells responsible for propagating the injury response. However, there is an emerging view that T lymphocytes can also regulate liver I/R-induced inflammation. Resident lymphocytes found within the liver include conventional 
ß TCR cells as well as unconventional NK and 
T cells. These lymphocytes can alter inflammation through the secretion of soluble mediators such as cytokines and chemokines or through cognate interactions in an antigen-dependent manner. Expression of these mediators will then result in the recruitment of more lymphocytes and neutrophils. There is evidence to suggest that T cell activation in the liver during I/R can be driven by antigenic or nonantigenic mechanisms. Finally, immune cells are exposed to different oxygen tensions, including hypoxia, as they migrate and function within tissues. The hypoxic environment during liver ischemia likely modulates T cell function, at least in part through the actions of hypoxia-inducible factor-1. Further, this hypoxic environment leads to the increased concentration of extracellular adenosine, which is generally known to suppress T cell proinflammatory function. Altogether, the elucidation of T lymphocyte actions during liver I/R will likely allow for novel targets for therapeutic intervention.
Key Words: liver • inflammation • T cells
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INTRODUCTION
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Ischemia/reperfusion (I/R) injury is a component of a number of clinical situations including stroke, shock, transplantation, and myocardial infarction. Despite important increases in medical care, prevention of I/R-related injuries continues to be problematic. I/R injury of the liver results most commonly from resection surgery, transplantation, and trauma. Following reperfusion, initiation of an acute inflammatory response is a key contributing factor, resulting in tissue injury. A significant portion of the injury is a result of leukocyte-dependent damage. The actions of Kupffer cells and neutrophils have been well studied and reviewed and are thought to be the cells responsible for initiating and propagating the injury response. However, there is an emerging view that T lymphocytes also regulate liver I/R-induced inflammation.
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ORIGIN OF HEPATIC T LYMPHOCYTES
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During development, the fetal liver acts as the primary site of erythropoiesis from mid-gestation. Just prior to birth, the bone marrow becomes active in the generation of hemopoietic cells. In the adult liver, 
30% of the liver’s cells are nonhepatocytes [1
]. These cells include stellate cells, endothelial cells, macrophages, dendritic cells (DC), and lymphocytes and give the liver the ability to generate a variety of acute-phase proteins, chemokines, and cytokines [2
].
Blood supply to the liver originates from the gut and contains endotoxins and foreign antigens from the gastrointestinal tract. Kupffer cells are derived from blood monocytes, which have become differentiated and localized to the liver. These cells represent a first line of defense to these antigens in that they have the ability to phagocytose normal amounts of antigens and endotoxins. If the amount of antigen exceeds the phagocytic capacity of the Kupffer cells, then DC located in the central veins and portal tract [3
] will bind the antigen and migrate to extrahepatic lymph nodes. Here, the DC will present portions of the antigen within the context of the MHC to T cells, which are specific toward the antigen. These antigen-specific T cells will expand in numbers and subsequently migrate to the liver. Here, they will interact with antigen-presenting Kupffer and endothelial cells to clear the foreign antigen. Once the challenge is cleared, more than 90% of the T cells will undergo apoptosis [4
], and some T cells will remain in the liver as memory T cells. As the liver ages, more T cells will accumulate such that in the average adult liver, there are 1010 resident lymphocytes [5
, 6
]. Other resident lymphocytes include NK T (NKT) cells and TCR-bearing cells. NKT cells are a subset of T cells, which coexpress an ß TCR but also express a variety of molecular markers, typically associated with NK cells, such as NK1.1 [7
]. They differ from conventional ß T cells in that their TCRs are far more limited in diversity and in that they recognize lipids and glycolipids presented by CD1d molecules, a member of the CD1 family of antigen-presenting molecules, rather than peptide-MHC complexes. TCR-bearing cells or T cells are preferentially localized in nonlymphoid tissues [8
]. Antigen recognition by T cells is limited as compared with conventional T cells, and the repertoire of natural ligands is not well developed [9
, 10
].
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HEPATIC LYMPHOCYTE FUNCTION
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Liver-resident T lymphocytes can alter inflammation through the secretion of soluble mediators such as cytokines and chemokines or through cognate interactions in an antigen-dependent manner. Table 1
lists the liver-resident lymphocytes as well as other resident leukocytes and the primary cytokines produced by each cell type. In general, lymphocytes can have a pro- or anti-inflammatory phenotype determined by the production of IFN- or IL-4. Hepatic T lymphocytes respond similarly, as ex vivo stimulation of liver resident mononuclear cells with a T cell-specific mitogen results in the production of IFN- and IL-4 (C. C. Caldwell, unpublished data). This indicates the presence of Th1 (or Tc1) and Th2 (or Tc2) cells in the liver and contrasts sharply with T cells taken from lung, peritoneum, or secondary lymphoid tissue, where T cell stimulation results predominantly in IFN- production (C. C. Caldwell, unpublished data). The manner in which T cell-derived IFN- affects the inflammatory response to liver I/R is not understood completely. However, IFN- stimulates Kupffer cells to produce TNF-, IL-1, and prostanoids [37
] and results in hepatocyte production of CC chemokines [38
]. Thus, it is likely that T cell release of IFN- contributes to the early induction of hepatic inflammation after I/R.
In contrast to IFN-, IL-4 is an important anti-inflammatory cytokine, which functions to terminate leukocyte proinflammatory actions [39
, 40
]. In the liver, IL-4 appears to suppress inflammation. For example, IL-4 counteracts the effect of IL-1 and IL-6 on the production of acute-phase proteins by hepatocytes [41
, 42
]. Therefore, IL-4 production may regulate the inflammatory actions of leukocytes and hepatocytes. Finally, other liver-resident leukocytes produce a variety of inflammatory mediators, which can contribute to or suppress hepatic inflammatory reactions through direct and indirect actions on lymphocyte function.
The cytokines TNF- and IL-6 are produced by T cells. IL-6 is a candidate downstream mediator of the protective and proproliferative effects of ischemic preconditioning against hepatic I/R [43
]. TNF- appears to be a critical but bifunctional mediator during hepatic I/R in that in its absence, liver I/R-mediated injury as well as priming for liver regeneration are blunted [44
]. During kidney I/R, increased intracellular cytokine production of TNF- by CD3+ T cells was found [45
]. Further, it was found that TCR-deficient mice had a significant, functional and structural protection, which in turn was associated with a decreased level of TNF- and IL-6 proteins in postischemic kidney tissue compared with wild-type mice [46
]. Although this remains to be shown during liver I/R, it is possible that modulation of TNF- and IL-6 expression by T cells could be used to mediate tissue damage, as well as subsequent regeneration.
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RECRUITMENT OF LYMPHOCYTES TO THE LIVER
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Chemokines play a key role in the trafficking and homing of leukocytes [47
]. During development and effector function, T lymphocytes have a differential expression of chemokine receptors. First, pre-thymocytes are induced by stromal cell-derived factor 1 via the thymocyte-expressing CXCR4 to migrate to the thymus for differentiation to thymocytes [48
, 49
]. The progression of the early thymocytes to naïve thymocytes includes the transcription of TCR-, rearrangement of TCR-ß, and expression of TCR on the surface. After this differentiation, the naïve T cells enter the circulation expressing CCR7, until they come into contact with their specific antigen, presented by an APC in secondary lymphoid tissues [50
]. Upon progression into effector cells, T cells no longer express CCR7 and depending on the antigenic stimulation, express a new repertoire of chemokine receptors. In general, a proinflammatory T cell will express CXCR3 and CCR5, and anti-inflammatory T cells will express CCR4, CCR8, and CCR3 [51
]. However, although the cytokine production of differentiated Th1 or Th2 cells depends mainly on the tissue of origin and the infection, chemokine receptor surface expression is an insufficient indicator of T cell trafficking [52
].
Significant involvement of T lymphocytes in hepatic I/R was first demonstrated in 1997 in a report, which found that T lymphocytes accumulated rapidly in the liver after reperfusion [53
]. This study showed that CD4, but not CD8, T lymphocytes were recruited into the postischemic liver within 1 h of reperfusion. The briskness of this response is surprising, as it preceded the influx of innate immune cells to the injured tissue. Later, studies by our group confirmed this rapid recruitment of CD4 T cells [54
]. The mechanisms by which T cells are recruited so rapidly to the postischemic liver remain undefined. However, other studies have shown that hepatic expression of MCP-1, MIP-1, MIP-1ß, MIP-2, RANTES, and IFN-inducible protein 10 (IP-10) is up-regulated 24 h after liver I/R [55
]. A summary of potential chemokines produced specifically during liver I/R and their receptors is listed in Table 2
. Most of the up-regulated chemokines are chemotactic to neutrophils and monocytes, except for RANTES, which is specific for T cells and has been implicated in lymphocyte recruitment to the liver [65
]. RANTES has been proposed as a major mediator of antigen-independent T lymphocyte activation [66
]. RANTES can initiate T lymphocyte signaling directly, initially, via a G protein-coupled pathway and later, via activation of a tyrosine kinase pathway [67
]. Other chemokine transcripts found to be elevated after liver I/R injury are CXCL9, -10, and -11, which are induced by IFN- and attract activated T lymphocytes and NK cells by binding to CXCR3 receptors [68
].
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REGULATION OF NEUTROPHIL RECRUITMENT BY CD4 T CELLS
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As mentioned above, CD4 lymphocytes are recruited into the postischemic liver long before any appreciable neutrophil accumulation. Antibody depletion of CD4 T cells and CD4 knockout mice showed reduced liver recruitment of neutrophils after I/R [53
, 54
]. The mechanism by which CD4 T cells regulate subsequent neutrophil accumulation appears to be related to their release of IL-17 (Fig. 1
), which is preferentially expressed and secreted by activated CD4 lymphocytes [69
]. Furthermore, in a model of peritoneal inflammation, IL-17 was found to mediate neutrophil recruitment by increasing the production of the chemokines MIP-2 and KC by the peritoneal mesothelium [70
]. IL-17 has also been shown to induce CXC chemokine production by other cell types, including epithelial cells, fibroblasts, osteoblasts, and endothelial cells [71
72
73
]. Our studies found that production of the CXC chemokine MIP-2 was decreased in CD4 knockout mice and that in wild-type mice treated with anti-IL-17 antibodies, MIP-2 production was also reduced [54
]. In both of these experiments, liver neutrophil accumulation was also reduced. Moreover, adoptive transfer of CD4 lymphocytes into CD4 knockout mice resulted in dramatic increases in the expression of MIP-2 and the degree of liver neutrophil recruitment [54
]. Thus, it would appear that CD4 lymphocytes are an important regulator of hepatic neutrophil recruitment during liver I/R and that this occurs via their release of IL-17 (Fig. 1)
.
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Figure 1. Putative model for involvement of CD4 cells in neutrophil recruitment. Following liver ischemia, CD4 T cells from the periphery accumulate in the liver (Step 1). These cells as well as resident liver CD4 T cells secrete IL-17, which act upon hepatocytes and macrophages to stimulate production of MIP-2, promoting the recruitment of neutrophils (Step 2).
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ANTIGENIC AND NONANTIGENIC STIMULATION OF T CELLS DURING LIVER I/R
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The question of whether T cell involvement in liver I/R is driven by antigenic or nonantigenic mechanisms has not been elucidated. Some studies show that use of MHC II-blocking antibodies has no effect on serum alanine transaminase following hepatic I/R [74
]. This study suggested that T cells play a beneficial role not involving the ß TCR and that lymphocyte actions occur through a nonantigenic mechanism. It is well established that during hepatic I/R, inflammatory cytokines such as IL-12 and IL-18 are expressed rapidly [75
, 76
]. Furthermore, non-naive as well as unconventional T cells can be functionally activated by these cytokines in a manner independent of TCR engagement [77
78
79
]. Taken collectively, these studies suggest the possibility of nonantigenic activation of T cells during the initial stages of I/R in the liver. Alternatively, recent studies in other models of I/R have discovered the presence of an IgM, which reacts with self-antigens generated by damaged tissues [80
, 81
]. These self-reactive IgMs activate the classical pathway of complement and contribute substantially to the initiation of the injury response. A similar mechanism may be applicable to liver I/R but to date, has not been examined.
To successfully mount an immune response to an antigen, T lymphocytes need to receive two different signals. The first signal is delivered by the antigen upon its binding to the TCR. This antigen-specific event is usually termed signal one. The second signal, signal two, is costimulation delivered by APC and is a nonantigen-specific event. There are a large number of different costimulatory molecules, and they vary greatly in their expression patterns and function [82
]. One of the most widely studied, costimulatory pathways is the CD40-CD154 pathway. CD40 is a member of the TNF receptor superfamily and is expressed on APC such as DC, macrophages, and B cells. Ligation of CD40 by its cognate ligand CD154 (which is transiently expressed on activated Th cells) leads to costimulation of the target cell. Specifically, during liver I/R, it has been shown that gene therapy-mediated CD154 blockade (Ad-CD40 Ig), antibody-induced systemic CD154 blockade (MR1 mAb), and genetically targeted CD154 absence (CD154 KO mice) ameliorated otherwise fulminant injury in a warm liver I/R model [83
]. These beneficial effects resulting from the disruption of CD154-CD40 signaling were accompanied by diminished liver T cell sequestration, decrease of vascular endothelial growth factor (VEGF) expression, inhibition of TNF- and Th type 1 cytokine production, and induction of antiapoptotic (Bcl-2/Bcl-xl) and depression of proapoptotic (caspase-3) proteins.
Another costimulatory pathway studied widely is the CD28/CD80/86 pathway. CD28 is constitutively expressed on T cells. The ligands for CD28 are CD80 and CD86 (B7-1, B7-2), members of the Ig superfamily, which are transiently expressed on activated APC. CD80 and CD86 are increased in the liver after I/R [84
, 85
]. Ligation of CD28 by these molecules in conjunction with antigen recognition via the TCR complex leads to activation of the T cell. An additional feature of this pathway is the existence of an alternative receptor for CD80/86—CD152 (CTLA-4)—which unlike CD28, is up-regulated after T cell activation and results in suppressive T cell function. Indirect evidence for a critical role for T cells in kidney I/R came from blocking one of the costimulatory pathways necessary for T cell activation. Blocking the B7-CD28 costimulation pathway by CTLA-4 Ig, a recombinant fusion protein, containing the extracellular domain of human CTLA-4 (a homologue of CD28), resulting in T cell anergy, ameliorated renal dysfunction and decreased mononuclear cell infiltration in a model of renal cold ischemia [86
]. It has yet to be elucidated whether such treatment during liver I/R would yield similar results.
The liver sinusoidal endothelial cell (LSEC) has been described as a new type of APC, which resides in the liver [87
, 88
]. LSEC are also believed to express the costimulatory moieties CD40, CD80, and CD86 and stimulate T cells through peptide presentation in the context of MHC Classes I and II molecules [80
, 89
]. This would allow endothelial activation by T cells and vice versa, as a result of TCR-MHC and CD40-CD154- or CD28-B7-dependent pathways. However, in a contrary report, which compared LSEC and DC directly, it was found that LSEC expressed surface markers only reflective of an endothelial phenotype. Further, highly purified LSEC had undetectable levels of the costimulatory receptors CD40, CD80, and CD86 and only minimal MHC Class II. This report concluded that LSEC are poor stimulators of T cells, but other properties, such as their high capacity for antigen uptake and direct access to circulating lymphocytes, may enable them to contribute to the unique, immunologic function of the liver [90
].
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EFFECT OF ISCHEMIA ON T CELL FUNCTION DURING LIVER I/R
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Immune cells are exposed to different oxygen tensions, including hypoxia, as they develop, migrate, and function in primary, secondary, and tertiary lymphoid organs with different infrastructure, vasculature, and oxygen supply [91
]. Hypoxic extracellular environments occur in some normal tissues and during chronic inflammation and ischemia. The mechanisms of lymphocyte adaptation to hypoxia are likely to exist under such conditions. Cell adaptation to hypoxia is accomplished partially by the transcriptional activity of hypoxia-inducible factor-1 (HIF-1), which is a basic helix–loop–helix/Per-aryl hydrocarbon receptor nuclear translocator (ARNT)-Sim protein consisting of HIF-1 and HIF-1ß subunits. HIF-1 activates the transcription of genes required for glucose metabolism, erythropoiesis, vascularization, and cell proliferation by binding to a cis-acting hypoxia-response element. The HIF-1 subunit may also affect cell metabolism and signaling by its ability to interact directly with other proteins such as p53, heat shock protein 90, and receptor for activated C kinase 1. Multiple roles of HIF-1 as a transcriptional factor and in protein–protein interactions complicate the understanding of its role in vivo. The HIF-1ß subunit is also known as ARNT and serves as a heterodimerization partner for other transcription factors [92
]. Oxygen-sensing mechanisms and the subsequent regulation of HIF-1 expression are the subject of intensive investigations. It has been shown that protein stability plays the most important role in control of HIF-1 expression. At high oxygen tensions, HIF-1 is targeted for destruction by an E3 ubiquitin ligase containing the von Hippel-Lindau tumor-suppressor protein (pVHL). In the currently accepted model, pVHL binds to the oxygen-dependent degradation domain located in the central region of HIF-1, which results in a subsequent degradation of HIF-1, mainly expressed under hypoxic conditions, but there is also evidence for the accumulation of HIF-1 under some normoxic conditions. These include the stabilization and transactivation of HIF-1 by reactive nitrogen- or oxygen-derived species radicals (RNS and ROS, respectively) [93
], cytokines (TNF- and IL-1ß) [94
], growth factors, such as the insulin growth factor [95
], and TCR activation [92
] (Fig. 2
). To study the effects of HIF on T cell signaling, Turka and co-workers [96
] examined T cells lacking the gene encoding pVHL, Vhlh. As germ-line deficiency in Vhlh results in embryonic lethality, mice were used containing a conditional Vhlh 2-lox allele. Deletion of Vhlh alone forces oxygen-independent stabilization of HIF-1 at an early point in T cell ontogeny and induces transcription of HIF-responsive genes. The results suggest that hypoxic- and nonhypoxic-mediated HIF stabilization may minimize the strength and duration of Ca2+ signaling by means of acceleration of cytoplasmic Ca2+ clearance. In lymphocytes, changes in Ca2+ signaling can mediate lymphocyte homeostasis and function [97
, 98
]. Thus, the hypoxic environment during liver ischemia likely modulates T cells, at least in part, through the actions of HIF-1.
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Figure 2. Impact of increased HIF-1 and adenosine (ADO) A2a receptor (A2aR) activity. During I/R, hypoxia, as well as RNS, ROS, TNF-, and TCR activation, increase in the tissue microenvironment. These stimuli have been reported to stabilize HIF-1. In leukocytes, increased HIF-1 activity has been shown to increase glycolysis and VEGF secretion and decrease apoptosis. Increased occupation of the adenosine A2aR is well known to activate cyclase (AC) which results in increased intracellular cAMP, protein kinase A (PKA) activity, and phospho (p)-CREB. This increased activity can result in increased production of IL-4 and IL-10 and/or decreased production of IFN-, IL-10, and TNF-.
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HYPOXIA, ADENOSINE, AND T LYMPHOCYTE FUNCTION
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Even short periods of hypoxia lead to the enhanced breakdown of adenine nucleotides to adenosine because of the decreased production of ATP and accumulation of AMP, which can be metabolized further to adenosine through dephosphorylation by the cytosolic-5'-nucleotidase. In addition to the substrate-dependent formation of adenosine via cytosolic- and ecto-nucleotidases, the extracellular adenosine concentrations may be potentiated further by preventing its reuse through the inhibition of salvage pathways, i.e., hypoxia-dependent inhibition of the enzyme, adenosine kinase, which rephosphorylates the nucleoside to AMP [99
]. This could be a significant source of extracellular adenosine in conditions of deep hypoxia. In the myocardium, for instance, adenosine formation is directly proportional to the AMP concentration. Under normoxic conditions, the adenosine formed is, in part, converted back into AMP by phosphorylation via the enzyme adenosine kinase. As the metabolic cycle between AMP and adenosine usually has a high turnover rate, any decrease in the adenosine kinase activity will translate automatically into enhanced adenosine formation, even when AMP concentrations are increased only slightly, e.g., by hypoxia [99
].
Studies about the potential role of extracellular adenosine in inflammation were facilitated by identification of four types of adenosine receptors. The A1 and A3 receptors are Gi protein-coupled, and A2a and A2b are Gs protein-coupled receptors, which can activate adenylate cyclase and cause accumulation of intracellular cAMP [100
]. Accumulation of adenosine during ischemia and inflammation can protect normal tissues from injury as a result of suppressive signaling through adenosine receptors (Fig. 2)
. mRNA expression studies strongly suggest that the A2aR is the major functional adenosine receptor, which attenuates activation of immune cells [101
]. Further, A2aRs have been shown to play a nonredundant role in the down-regulation of acute inflammation [102
].
Abundant evidence strongly suggest that adenosine, through the A2aR, can inhibit peripheral T cell activation, proliferation, and production of inflammatory cytokines while enhancing the production of anti-inflammatory cytokines in these cells [92
, 103
]. During liver I/R, the use of an A2aR-selective agonist, ATL146e, as well as a selective A2aR antagonist, ZM241385, and deletion of the A2aR gene show convincingly that A2aR activation during reperfusion reduces murine liver I/R greatly [56
]. ATL146e attenuated liver damage and inflammation, as assessed by serum glutamic pyruvic transaminase, edema, myeloperoxidase, histology, immunohistochemistry, and the reduced induction of proinflammatory cytokine and chemokine transcripts [104
, 105
]. A2aR agonist treatment during reperfusion can be delayed for up to 1 h with little attenuation of protection. This suggests that A2aR agonist-mediated protection occurs downstream of oxygen radical production, which occurs early after reperfusion. It was shown further that activation of the A2aR on bone marrow-derived cells is primarily responsible for protecting the liver from reperfusion injury.
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CONCLUSIONS
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Only the spleen surpasses the liver in terms of the number and variety of leukocytes. As such, the liver can be considered a quasi-lymphoid organ. Of the leukocytes found within the liver, lymphocytes have been shown recently to play a role in I/R, although the mechanism by which this occurs remains to be elucidated fully. Initially, during I/R, it appears that resident lymphocytes modulate inflammation by the production of cytokines, such as IFN-, IL-4, and/or IL-17, as well as the production of chemokines such as IP-10 and RANTES. Expression of these mediators will then result in the recruitment of more lymphocytes and neutrophils. As the phenotype of the recruited T cells has not been determined, the role of these cells in liver I/R is unclear. Finally, the most current evidence suggests that the actions of lymphocytes are occurring through a mechanism, which does not involve the ligation of a conventional ß or unconventional TCR. However, published data do not rule out the involvement of NKT cell interactions with the restricted CD1d MHC. Thus, it seems likely that lymphocyte actions are triggered by paracrine signals induced by the postischemic milieu.
Received January 24, 2007;
revised April 4, 2007;
accepted April 9, 2007.
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ABSTRACT
INTRODUCTION