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Journal of Virology, April 2003, p. 4004-4014, Vol. 77, No. 7
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.7.4004-4014.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

CC Chemokine Ligand 3 (CCL3) Regulates CD8⁺-T-Cell Effector Function and Migration following Viral Infection

Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, California 92697-3900,¹ Departments of Neurology and Pathology, Keck School of Medicine, University of Southern California, Los Angeles, California 90033,² Section of Molecular Genetics and Microbiology and Institute for Cellular and Molecular Biology, University of Texas, Austin, Austin, Texas 78712³

Received 17 June 2002/ Accepted 31 December 2002

Chemokines induce the directional migration of targeted populations of leukocytes during periods of inflammation. Moreover, these molecules also regulate T-cell activation and differentiation following antigenic stimulation. In the present study, the contributions of the CC chemokine ligand 3 (CCL3) to the differentiation and migration of effector T cells in response to viral infection of the central nervous system (CNS) were analyzed. CCL3^-/- mice infected with mouse hepatitis virus exhibited a significant reduction of virus-specific CD8⁺ T cells within the CNS, correlating with delayed viral clearance. Decreased infiltration of CD8⁺ T cells into infected CCL3^-/- mice was associated with enhanced accumulation of primed CD8⁺ T cells in cervical lymph nodes. Although virus-specific CD8⁺ T cells from CCL3^-/- mice were CD44^high, they remained CD62L^high and CD25^low, retained CCR7 expression, and contained limited transcripts of the proinflammatory chemokine receptors CCR5 and CXCR3 compared with virus-specific CD8⁺ T cells from CCL3^+/+ mice. Furthermore, the absence of CCL3 impaired the cytokine production and cytolytic activity of CD8⁺ T cells. In addition, macrophage accumulation within the CNS was significantly decreased in infected CCL3^-/- mice, correlating with reduced demyelination. These results suggest that CCL3 not only mediates macrophage chemotaxis but also significantly enhances differentiation of primed CD8⁺ T cells into effector cells and their release into circulation, thus potentiating effective migration to the site of infection.

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