Role for CXCR6 in Recruitment of Activated CD8 + Lymphocytes to Inflamed Liver Tohru Sato, Henrik Thorlacius, Brent Johnston, Tracy L. Staton, Wenkai Xiang, Dan R. Littman and Eugene C. This information is current as Butcher of September 27, 2021. J Immunol 2005; 174:277-283; ; doi: 10.4049/jimmunol.174.1.277 http://www.jimmunol.org/content/174/1/277 Downloaded from

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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 © 2005 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology

Role for CXCR6 in Recruitment of Activated CD8؉ Lymphocytes to Inflamed Liver1

Tohru Sato,2,3*†‡ Henrik Thorlacius,3,4*‡ Brent Johnston,5*‡ Tracy L. Staton,*‡ Wenkai Xiang,§ Dan R. Littman,§ and Eugene C. Butcher*‡

Hepatic infiltration of activated CD8 lymphocytes is a major feature of graft-vs-host disease (GvHD). Chemoattractant cytokines and their receptors are key regulators of lymphocyte trafficking, but the involvement of chemoattractant receptors in the phys- iologic recruitment of cells into the inflamed liver has not been defined. The present study examines the role of the chemokine receptor CXCR6, which is highly expressed by liver-infiltrating CD8 T cells. Hepatic accumulation of donor CD8, but not donor ؊/؊ b bxd CD4, lymphocytes was significantly reduced in GvHD induced by transfer of CXCR6 , H-2D lymphocytes into BDF1, H-2D recipients. To determine whether altered recruitment contributes to the reduced accumulation, CXCR6؊/؊ or wild-type splenic lymphocytes participating in an active GvHD response were isolated and transferred i.v. into secondary recipients with active Downloaded from (GvHD, and the short term (6-h) recruitment of transferred cells to the inflamed liver was assessed. CXCR6؊/؊ CD8 (but not CD4 cells displayed a significant (33%) reduction in liver localization, whereas frequencies in blood of CXCR6؊/؊ and wild-type CD8 cells were similar. Proliferation and apoptosis of liver-infiltrating donor CD8 cells were unaffected. We conclude that CXCR6 helps mediate the recruitment of activated CD8 lymphocytes in GvHD-induced hepatitis and may be a useful target to treat pathological inflammation in the liver. The Journal of Immunology, 2005, 174: 277–283. http://www.jimmunol.org/ onor T cell recruitment into target tissues is a prominent Ͼ20 chemokine receptors have been described (4). The role of component of graft-vs-host disease (GvHD),6 and a ma- specific chemokine receptors in attracting activated lymphocytes D jor complication in allogenic bone marrow transplanta- appears to be both stimulus and organ dependent, contributing to tion (1). Recruitment of activated lymphocytes is a multistep pro- inflammatory and homeostatic tissue localization of lymphocyte cess in which the expression of specific adhesion molecules and subsets (5). In GvHD the liver is a key target organ, characterized chemokine receptors endows lymphocytes with the ability to ac- by massive lymphocyte accumulation (6), which may reflect en- cess extravascular tissues (2). Chemokine receptors play a central hanced recruitment and/or proliferation. role in lymphocyte recruitment by rapidly transmitting intracellu- Acute GvHD is initiated by donor T cells recognizing and re- by guest on September 27, 2021 lar signals and triggering increased integrin affinity to adhesion acting to host allo-Ags and is characterized by a Th1-polarized molecule ligands displayed by endothelial cells (3). At present, response (7). Different combinations of chemokine receptors are associated with Th1- vs Th2-dependent immune reactions (8). Ac- cordingly, it has been shown that the chemokine receptor CXCR6 *Laboratory of Immunology and Vascular Biology, Department of Pathology, and †Department of Medicine, Stanford University School of Medicine, Stanford, CA (Bonzo/STRL33/TYMSTR) is expressed on T cells of Th1 phe- 94305; ‡Center for Molecular Biology and Medicine, Veterans Affairs Palo Alto notype (9–13). CXCR6, originally described as a novel simian § Health Care System, Palo Alto, CA 94304; and Howard Hughes Medical Institute immunodeficiency virus receptor (14) and fusion cofactor for and Molecular Pathogenesis Program, Skirball, Institute, New York University School of Medicine, New York, NY 10016 HIV-1 strains (15), is expressed at very low levels in naive CD8 Received for publication March 23, 2004. Accepted for publication October 22, 2004. cells (16, 17), but can be up-regulated in T cells by activated den- The costs of publication of this article were defrayed in part by the payment of page dritic cells (DC) (9–11). Moreover, it has been shown that many charges. This article must therefore be hereby marked advertisement in accordance Th1-polarized cells (13) and in vitro-activated CD8 cells (16) are with 18 U.S.C. Section 1734 solely to indicate this fact. attracted by the CXCR6 ligand, CXC ligand 16 (CXCL16; SR- 1 This work was supported by grants from the National Institutes of Health, the De- PSOX/SexCKine). In target tissues, CXCR6-expressing cells are partment of Veterans Affairs (to E.C.B.), and the FACS Core Facility of the Stanford Digestive Diseases Center. T.S. was supported by a K08 grant from the National readily found in the liver of patients with alcohol- or hepatitis Institutes of Health. H.T. was supported by the Swedish Research Council (2001- C-induced liver cirrhosis (9, 18). CXCL16 is abundantly expressed 6576, 2002-955, 2002-8012, and 2003-4661), Crafoordska stiftelsen, Blanceflors stif- telse, Einar och Inga Nilssons stiftelse, Harald och Greta Jaenssons stiftelse, Greta och in lymphoid and nonlymphoid tissues, such as the liver (13, 16, Johan Kocks stiftelser, Fro¨ken Agnes Nilssons stiftelse, Magnus Bergvalls stiftelse, 19). Furthermore, the kinetics of DC-mediated up-regulation also Mossfelts stiftelse, Nanna Svartz stiftelse, Ruth och Richard Julins stiftelse, Svenska suggest a role of CXCR6 in facilitating effector T cell migration La¨karesa¨llskapet, and Teggers stiftelse. into sites of pathological inflammation; CXCR6 is up-regulated, 2 Address correspondence and reprint requests to Dr. Tohru Sato, Veterans Affairs Palo Alto Health Care System, 3801 Miranda Avenue, MC154B, Palo Alto, CA whereas CCR7, a chemokine receptor involved in homing to 94304. E-mail address: [email protected] lymph nodes, is down-regulated after prolonged incubation with 3 T.S. and H.T. contributed equally to this work. DC under Th1-polarizing conditions (11). However, the role of 4 Current address: Department of Surgery, Lund University, Malmo University Hos- CXCR6 in lymphocyte recruitment in vivo is not known. pital, S-205 02, Malmo, Sweden. The aim of this study was to assess the contribution of CXCR6 5 Current address: Dalhousie University, Sir Charles Tupper Medical Building, Room to the recruitment of activated lymphocytes into inflamed liver. For 7C, 5850 College Street, Halifax, Nova Scotia, Canada B3H 1X5. this purpose we developed a short term, in vivo recruitment assay 6 Abbreviations used in this paper: GvHD