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CCR5 in T Cell-Mediated Liver Diseases: What's Going On? Maureen N. Ajuebor, Jillian A. Carey and Mark G. Swain This information is current as J Immunol 2006; 177:2039-2045; ; of September 29, 2021. doi: 10.4049/jimmunol.177.4.2039 http://www.jimmunol.org/content/177/4/2039 Downloaded from References This article cites 62 articles, 20 of which you can access for free at: http://www.jimmunol.org/content/177/4/2039.full#ref-list-1

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BRIEF REVIEWS

CCR5 in T Cell-Mediated Liver Diseases: What’s Going On?1 Maureen N. Ajuebor, Jillian A. Carey, and Mark G. Swain2

The chemokine receptor CCR5 came into worldwide Over the past 10 years, chemokines have been the focus of a prominence a decade ago when it was identified as one of great deal of research pertaining to their role in promoting leu- the major coreceptors for HIV infectivity. However, sub- kocyte trafficking and recruitment during inflammatory re- sequent studies suggested an important modulatory role sponses. It is perhaps not surprising that chemokines are often for CCR5 in the inflammatory response. Specifically, regarded as “the commander-in-chief” of leukocyte migration. CCR5 has been reported to directly regulate T cell function in autoimmune diseases, including multiple sclerosis, Chemokines Downloaded from rheumatoid arthritis, and type 1 diabetes. Moreover, T Chemokines are a large family of specialized heparin-binding cell-mediated immune responses are proposed to be critical proteins, the primary and traditional function of which is to in the pathogenesis of autoimmune and viral liver dis- regulate the trafficking of leukocytes (5, 6). These proteins can eases, and recent clinical and experimental studies have promote T cell differentiation to either Th1- or Th2-type responses by augmenting or directionally differentiating T cells also implicated CCR5 in the pathogenesis of autoimmune http://www.jimmunol.org/ and viral liver diseases. Therefore, in this brief review, we toward polarized type 1 or type 2 responses (5). Chemokines highlight the evidence that supports an important role of are subdivided into four subfamilies (C-X-C, C-C, C, and CCR5 in the pathophysiology of T cell-mediated liver dis- C-X3-C) based on their amino-terminal cysteine residues eases with specific emphasis on autoimmune and viral (6–8). To date, 43 human chemokines have been described previously (7, 8). liver diseases. The Journal of Immunology, 2006, 177: The biological actions of chemokines are mediated through a 2039–2045. family of seven transmembrane G protein-coupled receptors (GPCRs) present on the surface of target cells (6–9). Chemo- he liver contains a large population of resident lympho- kine receptors belong to a large superfamily of GPCRs, a diverse by guest on September 29, 2021 ϩ ϩ cytes, including CD8 and CD4 T cells; T cells that class of cell surface receptors that include receptors for neuro- T are crucial elements in the adaptive immune response. transmitters and proteinases. Presently, 19 different human Furthermore, NK and NKT cells, which are key components of chemokine receptors have been characterized (6–9). Specifi- the innate immune system, are highly enriched in the liver cally, 6 C-X-C chemokine receptors, designated CXCR1 to (Refs. 1 and 2; Fig. 1). Thus, the liver plays a critical role in the CXCR7, and 11 C-C chemokine receptors, denoted CCR1 to first-line host defense against incoming foreign Ags absorbed CCR11, are known (6–9). Receptors for lymphotactin (XCR1) from gut, where it maintains a balance between tolerance and and fractalkine (CX3CR1) have also been characterized (7, 8). generation of an immune response. Disruption of this balance through multiple mechanisms, including T cell activation, CCR5 chemokine receptor could potentially lead to the development of liver diseases. T The CCR5 chemokine receptor is a CC chemokine receptor cell-mediated liver diseases, including viral liver diseases (such that is expressed on many cell types, including NKT cells, 3 ϩ ϩ as hepatitis B virus (HBV) and hepatitis C virus (HCV)), au- CD4 T cells, CD8 T cells, and macrophages (7, 8, 10, 11). toimmune hepatitis (AIH), and graft-vs-host disease CCR5 mediates its biological effects by interacting with any of (GVHD)), affect Ͼ300 million people worldwide (3, 4) What- these three ligands: CCL3, CCL4, and CCL5 (6, 8, 11). CCR5 ever the stimulus for development of T cell-mediated liver dis- is preferentially expressed on Th1 cells (11, 12), suggesting that eases, the final common pathway is an influx and activation of T this receptor may be important in the recruitment of IFN-␥- ϩ ϩ ϩ cells (CD4 , CD8 , NKT cells, and regulatory T (Treg) cells) producing CD4 T cells to inflammatory sites; however, this in the liver. remains controversial (13).

Gastrointestinal Research Group, Faculty of Medicine, University of Calgary, Calgary, Al- for Medical Research Senior Scholar and a CIHR/Health Canada Hepatitis C Initiative berta, Canada Investigator. J.A.C. is supported by a Canadian Liver Foundation studentship. Received for publication April 25, 2006. Accepted for publication May 26, 2006. 2 Address correspondence and reprint requests to Dr. Mark G. Swain, Faculty of Medicine, University of Calgary, 3330 Hospital Drive Northwest, Calgary, Alberta T2N 4N1, Can- The costs of publication of this article were defrayed in part by the payment of page charges. ada. E-mail address: [email protected] This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 3 Abbreviations used in this paper: HBV, hepatitis B virus; HCV, hepatitis C virus; AIH, autoimmune hepatitis; GVHD, graft-vs-host disease; Treg, regulatory T; GPCR, G pro- 1 Our work cited in this review was funded by the Canadian Institutes for Health Research tein-coupled receptor; KO, knockout; FasL, Fas ligand. (CIHR)/Health Canada Hepatitis C Initiative. M.G.S. is an Alberta Heritage Foundation

FIGURE 1. Lymphocyte composition in the mouse and human liver as determined by specific cell surface markers and analyzed by flow cytometry. Adapted from Refs. 1, 2, 4. Downloaded from

The CCR5 receptor came to worldwide attention about a de- with particular emphasis on viral liver disease (HCV), AIH, and cade ago after being identified as one of the major coreceptors GVHD. Specifically, we provide information from the clinical for HIV infectivity, and CCR5 ligands were noted to possess and experimental setting demonstrating the beneficial (good) anti-HIV activity (14). The observation that Caucasian indi- or detrimental (bad) role of CCR5 during T cell-mediated he- http://www.jimmunol.org/ viduals who have a natural CCR5 mutation, CCR5⌬32 (i.e., a patic inflammatory response. 32-bp deletion in this gene results in a nonfunctioning receptor that is trapped in the endoplasmic reticulum and therefore not Autoimmune hepatitis expressed at the cell surface), resist HIV infection (14, 15) fur- AIH is a progressive inflammatory liver disease that predomi- ther highlighted the fundamental role of CCR5 in HIV patho- nantly affects women. Although the factors that initiate and genesis. In the last decade, significant progress has also been regulate AIH remain poorly defined, there is evidence AIH is ϩ made in the development of CCR5 antagonist as potential ther- primarily initiated by CD4 T cells and to a lesser extent by ϩ apies for HIV infectivity. Regrettably, recent early clinical trials CD8 T cells that recognize self-Ag (4). It is well established by guest on September 29, 2021 ϩ of some CCR5 antagonists were abruptly halted due to pro- that CD4 T cells primarily function as regulators of other im- found hepatotoxicity (16–18), implicating CCR5 as poten- mune cells, either through secreted cytokines (e.g., Th1 or Th2) tially modulating the hepatic inflammatory response. In agree- or by direct cell-cell contact (23). However, splitting complex ment with CCR5 deficiency modulating the hepatic diseases such as AIH, in terms of Th1 and Th2 patterns, is likely inflammatory response, the CCR5⌬32 mutation was recently an oversimplification. Importantly, IL-4 (a cytokine classically reported to exacerbate the severity of hepatic inflammation and grouped as Th2) exerts proinflammatory effects in the liver. For injury in some T cell-mediated liver diseases (discussed below). example, direct expression of IL-4 in the liver of mice using re- In addition, CCR5 has also been implicated in the pathology of combinant adenoviruses coding for mouse IL-4 causes a lethal numerous autoimmune diseases, including multiple sclerosis, and dose-dependent hepatitis (24), and rIL-4 treatment of rheumatoid arthritis, and type 1 diabetes (19). mouse primary hepatocytes is known to cause apoptosis of these cells in vitro (24). Furthermore, T cell subtypes other than ϩ The role of CCR5 in T cell-mediated liver diseases: “the good and the bad” CD4 T cells can also produce both IFN-␥ and IL-4. There are a number of ways CCR5 could potentially modulate NKT cells are a unique T cell lineage that are defined as cells the hepatic inflammatory response in T cell-mediated liver dis- that coexpress the NK cell marker (usually NK1.1) and a highly eases. First, since T cell-mediated immune responses play a crit- restricted TCR specific for glycolipid Ag (25). NKT cells have ical role in hepatocyte damage induced by autoimmunity and the unusual property of recognizing glycolipid Ags in conjunc- viral infection and CCR5 is preferentially expressed on Th1 tion with the MHC class I-like molecule, CD1d, and are abun- cells (5, 11, 12), it was inferred that CCR5 could modulate he- dant in the liver (Fig. 1; Refs. 1, 2, 25). NKT cells are regarded patocyte damage during T cell-mediated liver diseases by pro- as a bridge between the innate and adaptive immune systems moting the recruitment of Th1-expressing cells to the liver. Sec- (26). In recent years, a growing body of evidence has demon- ond, CCR5 deficiency in humans, as well as in experimental strated that NKT cells are prime targets for immunomodula- animal models of inflammation and infection, is associated with tion due to their ability to secrete high levels of cytokines, in- significant increases in tissue levels of the CCR5 ligand CCL5 cluding IFN-␥ and IL-4, within minutes of activation (25, 26). (14, 20, 21). Therefore, these elevated tissue levels of CCL5 Interestingly, clinical and experimental studies have associated could in turn promote enhanced influx of leukocytes (including IL-4 produced by activated hepatic NKT cells with a more ag- T cells) into tissues by binding to its alternate receptor, CCR1, gressive hepatic injury in children with AIH and in experimen- expressed on these cells (20–22). tal AIH (27, 28). In this brief review, we discuss the evidence implicating The expression pattern of CCR5 in liver samples or blood CCR5 in the pathophysiology of T cell-mediated liver diseases specimens of patients with AIH remains unknown; however, The Journal of Immunology 2041 levels of CCL3, a CCR5 ligand, are increased in liver biopsies of ministration. Given that we have recently demonstrated that ϩ patients with AIH (29). Given that CCL3 plays an important CCR1-expressing CD4 T cells recruited to the liver produce role in promoting IFN-␥ production (5), this chemokine could IFN-␥ during Con A-induced hepatitis in normal mice (30), it potentially promote the development of AIH in humans by en- is likely that an augmented Th1 response via IFN-␥ production ϩ ϩ hancing IFN-␥ secretion from activated CD4 T cells similar by CCR1-expressing CD4 T cells directly contributes to the to what has been observed in experimental T cell-mediated hep- severe hepatitis observed in CCR5 KO mice during Con A-in- atitis (30). Currently, an ideal animal model of AIH does not duced hepatitis (22). In wild-type mice, NK cells do not appear exist. However, many of the important insights regarding the play a role in the development of Con A hepatitis (28). How- potential functional role of CCR5 in the pathology of AIH have ever, in follow-up to our initial study, we have recently observed been derived primarily from a murine model of T cell-mediated that CCR5 deficiency unmasks a potent proinflammatory role hepatitis (the Con A model of hepatitis) in which genetic dele- for NK cells during Con A-induced hepatitis (32). Specifically, tion of the CCR5 gene was examined for its effect on disease IL-4 produced by activated CCR5-deficient hepatic NKT cells development and severity. Although the Con A hepatitis model drives NK cell transactivation, resulting in augmented IFN-␥ is not truly a model of autoimmunity because there is no Ag production by NK cells, and specific depletion of IFN-␥ or NK specificity, Con A-induced hepatitis is a well-characterized mu- cells leads to a marked reduction in hepatitis in Con A-treated rine model of experimental T cell-mediated hepatitis and is felt CCR5 KO mice (32). Taken together, these studies (summa- to mimic many aspects of human AIH (10, 28, 30, 31), includ- rized in Fig. 2) suggest that: first, CCR5 signaling negatively ϩ ing the increased recruitment of activated CD4 T cells to the regulates activated hepatic NKT cell IL-4 production during Downloaded from liver and the development of a hepatic Th1 cytokine response, Con A-induced hepatitis in wild-type mice because enhanced which plays a central role in the development of hepatitis. Con hepatitis in CCR5 KO mice after Con A administration was A hepatitis is mediated by activated resident hepatic NKT cells, associated with exaggerated NKT cell IL-4 production; a find- ϩ which produce mainly IL-4 (28), and also by activated CD4 T ing that was confirmed by in vitro studies (10). Second, IL-4 cells recruited to the liver, which produce IFN-␥ (30). Cyto- produced by activated NKT cells subsequently transactivates kines, including IL-4 and IFN-␥, exert proinflammatory effects NK cells to exert proinflammatory effects via augmented IFN-␥ http://www.jimmunol.org/ during Con A-induced hepatitis (28). It is noteworthy that pre- production in Con A-treated CCR5 KO mice. Third, in the vious studies have demonstrated that CD1d knockout (KO) absence of CCR5, increased hepatic levels of the CCR1/CCR5 and V␣14 KO mice (which have very few NKT cells) and ligand CCL5 recruits mononuclear cells, including NK cells ϩ CD4 T cell KO mice all resist Con A-induced hepatitis (28). (22, 33), to the liver by interacting with its alternate receptor In support of a role for CCR5 in AIH, we (10) and others CCR1 and induces a Th1 response via augmented IFN-␥ pro- ϩ (22) have recently demonstrated that CCR5 KO mice, when duction by NK cells and CD4 T cells (32) within the liver. treated with Con A, are highly susceptible to the development of severe hepatitis and subsequent liver failure, relative to wild- by guest on September 29, 2021 type mice. Two unique mechanisms were proposed for these observations (10, 22). In the first study, we demonstrated that activated hepatic CCR5-deficient CD1d tetramer-positive NKT cells resist apoptosis after Con A administration and produce more IL-4 than wild-type controls (10). In addition, in vivo depletion of IL-4 or NKT cells ameliorated liver damage in CCR5 KO mice post-Con A treatment (10). Interestingly, the augmented IL-4 production by CD1d tetramer-positive hepatic NKT cells in Con A-treated CCR5 KO mice was not associated with a corresponding deficiency in IFN-␥ production by activated NKT cells (10); therefore, it is likely that the increased survival of CCR5-deficient CD1d tetramer-positive NKT cells together with enhanced IL-4 production is important in the development of liver failure in these mice (10). In support of this hypothesis, stimulation of isolated CCR5-deficient CD1d tetramer-positive NKT cells with Con A or anti- FIGURE 2. Summary of the effects of CCR5 deficiency in the Con A-in- CD3 mAb in vitro caused enhanced IL-4 production by these duced hepatitis. In the specific setting of CCR5 deficiency, Con A activation of cells relative to similarly stimulated wild-type NKT cells (10). hepatic NKT cells produces both IL-4 and IFN-␥; however, IL-4 production is ␥ Of note, IL-4 is known to promote hepatocyte damage in Con 2-fold higher than that observed in wild-type mice. IFN- in turn activates NK cells, resulting in additional IFN-␥ production, which ultimately promotes he- A hepatitis through increased Fas ligand (FasL) expression on patocyte death. IL-4 produced by activated NKT cells promotes hepatocyte NKT cells (28). Interestingly, we observed that CCR5 defi- death in a number of ways: 1) IL-4 directly increases FasL expression on NKT ciency augments FasL expression on isolated NKT cells after cells, and NKT cells in turn kill hepatocytes by interacting with Fas expressed rIL-4 treatment in vitro (10). on hepatocytes; 2) IL-4 transactivates NK cells, which subsequently produce In the second study, Moreno et al. (22) demonstrated that IFN-␥; and 3) IL-4 induces the production of CCL5 from cells within the liver ϩ (e.g., Kupffer cells), and CCL5 in turn promotes the recruitment of NK and enhanced recruitment of CCR1-expressing CD4 T cells, ϩ ϩ NKT cells (identified as simply NK1.1 cells), and macro- CD4 T cells from the blood into the liver. Additionally, the recruitment and activation of NK cells within the liver leads to the subsequent further recruit- phages to the liver of Con A-treated CCR5 KO mice, mediated ment of CD4ϩ T cells into the liver, which produce IFN-␥ and further prop- by the CCR1/CCR5 ligand CCL5, plays a central role in the agate liver injury. Adapted from Refs. 10, 22, 30, 32, 33. Recruitment is de- development of severe hepatitis in these mice after Con A ad- noted by a broken line (- - - -), whereas a straight line (—) represents activation. 2042 BRIEF REVIEWS: CCR5 IN T CELL-MEDIATED LIVER DISEASE—WHAT’S GOING ON?

Finally, an alternative possible explanation of the enhanced sus- cells and improved liver damage in nonirradiated recipient mice ceptibility of CCR5 KO mice to Con A-induced hepatitis is the (39). Surprisingly, IFN-␥ production by liver-infiltrating T potential failure of endogenous hepatic anti-inflammatory cells was not reduced by blocking CCR5, suggesting that IFN-␥ mechanisms (such as IL-10, an anti-inflammatory cytokine in may not necessarily be critical for the induction of liver injury Con A-induced hepatitis (34)) to curb the inflammatory re- during GVHD in nonirradiated mice (39). It is noteworthy sponse in these mice. However, we have observed similar he- that while a Th1 response via IFN-␥ production was previously patic levels of IL-10 in CCR5 KO mice relative to wild type associated with the development of GVHD in both nonirradi- during Con A-induced hepatitis (M. N. Ajuebor and M. G. ated and irradiated (i.e., conditioned) recipient mice, in recent Swain, unpublished observation). years, the role of IFN-␥ in GVHD pathogenesis has become less As mentioned previously, a substantial body of evidence has clear and more complicated than previously thought (35, 39, previously suggested a proinflammatory role for CCR5 in pro- 41). Despite this, STAT4, a signaling molecule that promotes moting the development of autoimmune diseases such as type 1 Th1 responses, was shown to contribute to the development diabetes and rheumatoid arthritis by augmenting Th1 re- and severity of GVHD in irradiated recipient mice (41). The sponses. However, recent studies suggesting that CCR5 signal- reason underlying this discrepancy in the development of a Th1 ing also exerts an anti-inflammatory role in autoimmunity (as response remains undefined and needs further detailed investi- shown in Con A-induced hepatitis) conforms with a previous gation. Further support of a proinflammatory role for CCL3 in observation in the viral influenza A virus (20) infectious model. GVHD derives from the observation that the transfer of CCL3-

deficient donor T cells caused a significant reduction in the in- Downloaded from ϩ GVHD flux of CD8 T cells into the liver coupled with reduced liver pathology in recipient mice (42). Of note, CCL3 has been GVHD is an immunologically mediated complication of bone ϩ marrow transplantation that often affects the liver and other shown to be produced by liver-infiltrating CD8 T cells during organ system (35). The liver disease associated with GVHD experimental GVHD (43). For this reason, it seems likely that ϩ is often described as a T cell-mediated liver disease based on CCL3 produced by CD8 T cells recruited to the liver recruits ϩ the fact that T cells have been implicated as key mediators in additional CD8 CTLs to the liver via CCR5 and conse- http://www.jimmunol.org/ the pathophysiology of GVHD. Specifically, GVHD is quently promotes liver damage during GVHD. ϩ caused by infiltrating donor T cells (primarily CD8 T cells) Although the proinflammatory effects of CCR5 in the patho- attacking Ags expressed on recipient cells (35). In support of genesis of GVHD have been well documented, it is becoming this is the observation that inflammatory infiltrates com- increasingly clear that CCR5 can also suppress inflammatory ϩ posed of donor T cells (mainly CD8 T cells) are found in responses during GVHD. In particular, the transfer of CCR5- lesions of patients with GVHD (35), and the depletion of deficient donor T cells into irradiated (i.e., conditioned) recip- ϩ CD8 T cells from donor T cells before transfer into the ient mice was reported to exacerbate GVHD, in association ϩ recipient reduces the incidence of GVHD in the clinical set- with an increase of donor CD8 T cell infiltrates in the liver by guest on September 29, 2021 ting (36). Many factors can potentially promote the genera- (44). Therefore, the functional role of CCR5 during GVHD tion of a Th1 response, but T cells are widely regarded as a appears to be model dependent since in nonirradiated recipient central figure in promoting Th1 responses via IFN-␥ pro- mice CCR5 blockade inhibits the hepatic inflammatory reduction (37). Since increased expression of IFN-␥ has been sponse, whereas in irradiated recipient mice, CCR5 blockade controversially associated with the progression of GVHD in enhances the hepatic inflammatory response. These findings both humans and experimental animal models (35), it has suggest that the CCR5⌬32 mutation could possibly predispose ϩ been proposed that the recruitment of donor CD8 T cells conditioned (i.e., irradiated) patients to the occurrence of from the blood to the site of liver injury during GVHD GVHD after stem cell transplantation. could be potentially explained by increased expression of A potential mechanism that could account for CCR5 block- CCR5, a chemokine receptor that is preferentially expressed ade enhancing the hepatic inflammatory response in irradiated on Th1 cells. Moreover, increased CCR5 expression has mice during GVHD may include a reduced CCR5-mediated ϩ ϩ been observed in peripheral blood buffy coats of patients accumulation of Treg cells (CD4 CD25 T cells) within the with GVHD (38). liver (45). In agreement with this hypothesis, CCR5-deficient Evidence for a role of CCR5 in the pathology of GVHD has Treg cells are unable to suppress GVHD-induced lethality, and come from a number of studies using experimental murine this observation correlates with the reduced hepatic accumula- models of GVHD. Specifically, increased expression of CCR5 tion of CCR5-deficient Treg cells, as compared with wild-type ϩ on recruited donor T cells (mainly CD8 T cells) in the liver of Treg cells, in GVHD (45). Naturally occurring Treg cells are ϩ nonirradiated (i.e., unconditioned) recipient mice was observed CD4 T cells that mature in the thymus, represent 5–10% of ϩ during GVHD (39). Furthermore, treatment of the nonirradi- the peripheral CD4 T cell population, and are characterized ated recipient mice with an anti-CCR5 blocking Ab markedly by the constitutive expression of the transcription factor Foxp3 reduced liver damage in association with the reduced recruit- (46). Interestingly, both mice and humans deficient in a func- ϩ ment of both CCR5-expressing CD8 T cells and FasL expres- tional Foxp3 protein suffer from severe autoimmune disease ϩ sion on CD8 T cells in the liver during GVHD (39). Al- (46). An alternative mechanism underlying the enhancement of though the CCR5 ligands (CCL3, CCL4, and CCL5) are the hepatic inflammatory response after CCR5 blockade in ir- differentially increased in the liver during GVHD (39, 40), radiated mice during GVHD could potentially include a re- CCL3 has emerged as a central figure for inducing the recruit- duced CCR5-mediated accumulation of NKT cells within the ϩ ment of CCR5-expressing CD8 T cells into liver during liver. Specifically, a recent study reported a correlation between GVHD. Specifically, anti-CCL3-neutralizing Ab treatment in- the reduced hepatic accumulation of NKT cells with the pro- ϩ hibited the hepatic infiltration of CCR5-expressing CD8 T gression of GVHD (47). Therefore, the role of CCR5 in NKT The Journal of Immunology 2043 cell accumulation in the liver during GVHD in irradiated mice HCV infection (50). In agreement with this, increased expres- warrants further investigation. sion of CCR5 ligands (CCL3, CCL4, and CCL5) and their receptor, CCR5, has been observed in the livers of patients in- Viral liver diseases fected with HCV (11, 54). Accordingly, it was hypothesized HBV and HCV are hepatotropic viruses that replicate mainly that CCR5 interacts with its ligands expressed in the liver to in the liver. In both infections, liver damage occurs as a conse- promote the recruitment of Th1-expressing cells into the liver quence of the immune response to virus present within the liver. to mediate the clearance of HCV-infected hepatocytes (11, 54). Over 300 million people worldwide are persistently infected Concurrent with this finding was the observation that reduced ϩ with HBV and HCV and risk developing chronic liver disease, CCR5 expression on CD8 T cells (due to receptor internal- cirrhosis, and hepatocellular carcinoma. Despite many com- ization) by the HCV structural protein E2 after interaction with mon features in their pathogenesis, HBV and HCV differ CD81 (a cell surface receptor that is widely expressed on hepa- markedly in their virological properties, as well as in their im- tocytes where it is a coreceptor for HCV binding (55)) dimin- mune escape and survival strategies (reviewed by Ref. 3). Al- ished Th1 responses and sustained chronic HCV infection (56, though HBV is a DNA virus whereas HCV is an RNA virus, 57). However, this finding remains controversial because an in- ϩ ϩ ϩ similar cell types (including NKT cell and CD8 and CD4 T crease in the number of CCR5-expressing CD8 T cells has cells) have been implicated in the pathogenesis of both liver dis- also been associated with increased inflammatory activity dur- eases (3). Although, animal models of HBV infection are well ing chronic HCV infection (58). Regardless, the accepted characterized (reviewed by Ref. 3), the role of CCR5 in the dogma is that a strong antiviral Th1 driven immune response is Downloaded from pathogenesis of clinical and experimental animal models of associated with viral clearance during acute HCV infection. HBV infection remains undetermined (and represents a poten- Moreover, antiviral therapy with IFN-␣ containing regimens tial fertile ground for investigation). Therefore, in this review, effectively treats some individuals with chronic HCV infection. we will specifically discuss the role of CCR5 in the pathophys- Interestingly, the efficacy of IFN-␣ has been attributed to its iology of viral hepatitis induced by HCV. ability to partially up-regulate CCR5 expression on T cells dur- http://www.jimmunol.org/ Hepatitis C virus ing HCV infection (59). In addition, ribavirin (a nucleoside an- alog used with IFN to treat HCV infection) is believed to be The cellular immune response is thought to play a key role in effective in HCV treatment in part by biasing the hepatic cyto- the pathogenesis of HCV infection. Specifically, cells of innate ϩ ϩ kine profile to a Th1 response (60). (NK and NKT cells), as well as adaptive (CD4 and CD8 T The observation that down-regulation of CCR5 expression cells) immunity, have been implicated in the pathogenesis of on T cells impedes the clearance of HCV-infected hepatocytes acute and chronic HCV infection (48). It is broadly accepted during HCV infection led to the proposal that CCR5-deficient that these different cell types are key figures in promoting Th1 individuals may be prone to an increased susceptibility to HCV responses since they can promptly induce the secretion of by guest on September 29, 2021 infection. Indeed, the frequency of the CCR5⌬32 mutation IFN-␥ once activated (23, 25, 26). Based on this, it was pro- was reported to be 3-fold higher in patients with chronic HCV posed that these cells could potentially curtail viral replication infection relative to healthy controls (61). Specifically, the and hepatic injury during acute and chronic HCV infection by CCR5⌬32 mutation was associated with increased viral load promoting Th1 responses via IFN-␥ production. In agreement ϩ ϩ and CD8 T cell counts in the peripheral blood in a specific with this hypothesis, an increased CD8 T cell response via group of patients with hemophilia who were coinfected with IFN-␥ production was associated with viral clearance and re- HCV (but remained HIV free) (61). However, this study re- covery from acute HCV infection in patients (49) and in chimpanzees (50). Furthermore, a genetic predisposition to en- mains controversial because a number of studies have emerged ␥ with contradictory data. For example, other investigators have hanced NK cell function (through IFN- production) was ⌬ reported to contribute to the spontaneous clearance of HCV in reported that the CCR5 32 mutation did not correlate with an infected individuals (51). In contrast to acute HCV infection, increased incidence or severity of HCV infection (62, 63). A the development of persistent chronic HCV infection has been possible explanation for this discrepancy may be attributed to correlated with an impaired Th1 response (i.e., reduced IFN-␥ the fact that increased severity in HCV infection due to ϩ ⌬ production) due to defective CD8 T and NK cell responses CCR5 32 mutation was specific to a group of patients with during HCV infection (49, 52). Impaired NKT cell function hemophilia in the study by Woitas et al. (61). Interestingly, the ⌬ has also been reported to promote HCV chronicity (53). Spe- CCR5 32 mutation has been associated with reduced portal cifically, human CD1d-restricted NKT cells have been re- inflammation and more advanced fibrosis in HCV-infected pa- ported to favor a Th1 bias (by producing IFN-y but not IL-4) tients (64). These data are supported by the data showing that during HCV infection; however, the numbers of these cells polymorphism at Ϫ403 of the CCL5 gene promoter (which re- were observed to be lower in the liver of HCV-infected individ- sults in increased CCL5 gene transcription) is also associated uals relative to healthy individuals (53). with reduced portal inflammation in HCV-infected individuals The conventional view of chemokines is that they contribute (64). In light of the contradicting results from different studies, to the pathology of infectious and autoimmune diseases by pro- the precise role of CCR5 in HCV infection awaits further moting the recruitment of leukocytes to sites of tissue injury. elucidation. Small animal models of HCV infection are not widely available In summary, the role of CCR5 in antiviral immunity in liver (48). However, data from HCV-infected chimpanzees demon- disease remains undefined due to the lack of appropriate animal strating increased chemokine (including CCL2, CCL4, CCL5, models. It will be of interest to see ultimately whether observa- and CXCL10) expression in the HCV-infected liver suggest a tions made in CCR5-deficient mice treated with Con A will be potential role for these chemokines in the pathophysiology of paralleled in animal models of HCV infection in the future. 2044 BRIEF REVIEWS: CCR5 IN T CELL-MEDIATED LIVER DISEASE—WHAT’S GOING ON?

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