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Journal of Virology, February 2007, p. 1241-1250, Vol. 81, No. 3
0022-538X/07/$08.00+0     doi:10.1128/JVI.01937-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

CXCR3-Dependent Recruitment of Antigen-Specific T Lymphocytes to the Liver during Murine Cytomegalovirus Infection{triangledown}

Kirsten L. Hokeness,1,{dagger} Elizabeth S. Deweerd,1,{dagger} Michael W. Munks,2,{ddagger} Casey A. Lewis,1 Ronald P. Gladue,3 and Thais P. Salazar-Mather1*

Department of Molecular Microbiology and Immunology, Division of Biology and Medicine, Brown University, Providence, Rhode Island 02912,1 Department of Molecular Microbiology and Immunology, Oregon Health and Science University, Portland, Oregon 97239,2 Pfizer Global Research and Development, Department of Immunology, Eastern Point Road, Groton, Connecticut 063403

Received 5 September 2006/ Accepted 6 November 2006

Innate inflammatory events promoting antiviral defense in the liver against murine cytomegalovirus (MCMV) infection have been characterized. However, the mechanisms that regulate the selective recruitment of inflammatory T lymphocytes to the liver during MCMV infection have not been defined. The studies presented here demonstrate the expression of monokine induced by gamma interferon (IFN-{gamma}; Mig/CXCL9) and IFN-{gamma}-inducible protein 10 (IP-10/CXCL10) in liver leukocytes and correlate their production with the infiltration of MCMV-specific CD8 T cells into the liver. Antibody-mediated neutralization of CXCL9 and CXCL10 and studies using mice deficient in CXCR3, the primary known receptor for these chemokines, revealed that CXCR3-dependent mechanisms promote the infiltration of virus-specific CD8 T cells into the liver during acute infection with MCMV. Furthermore, CXCR3 functions augmented the hepatic accumulation of CD8 T-cell IFN-{gamma} responses to MCMV. Evaluation of protective functions demonstrated enhanced pathology that overlapped with transient increases in virus titers in CXCR3-deficient mice. However, ultimate viral clearance and survival were not compromised. Thus, CXCR3-mediated signals support the accumulation of MCMV-specific CD8 T cells that contribute to, but are not exclusively required for, protective responses in a virus-infected tissue site.

* Corresponding author. Mailing address: 69 Brown Street, Box G-B6, Brown University, Providence, RI 02912. Phone: (401) 863-9775. Fax: (401) 863-1971. E-mail: Thais_Mather{at}brown.edu.

{triangledown} Published ahead of print on 15 November 2006.

{dagger} These authors contributed equally to this work.

{ddagger} Present Address: Howard Hughes Medical Institute and National Jewish Medical and Research Center, Denver, CO 80206.

Journal of Virology, February 2007, p. 1241-1250, Vol. 81, No. 3
0022-538X/07/$08.00+0     doi:10.1128/JVI.01937-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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