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CCR5 in T Cell-Mediated Liver Diseases: What's Going On? Maureen N 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 Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on September 29, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2006 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. THE JOURNAL OF IMMUNOLOGY 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 func- tion 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 re- sponses 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 Copyright © 2006 by The American Association of Immunologists, Inc. 0022-1767/06/$02.00 2040 BRIEF REVIEWS: CCR5 IN T CELL-MEDIATED LIVER DISEASE—WHAT’S GOING ON? 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.
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