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The Journal of Neuroscience, May 19, 2004, 24(20):4849-4858; doi:10.1523/JNEUROSCI.0123-04.2004
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Cellular/Molecular
Efficient T-Cell Surveillance of the CNS Requires Expression of the CXC Chemokine Receptor 3
Jeanette Erbo Christensen,1 Anneline Nansen,1 Torben Moos,2 Bao Lu,3 Craig Gerard,3 Jan Pravsgaard Christensen,1 andAllan Randrup Thomsen1 1Institute of Medical Microbiology and Immunology and 2Department of Medical Anatomy, University of Copenhagen, Copenhagen, Denmark, and 3Ina Sue Perlmutter Laboratory, Children's Hospital and Harvard Medical School, Boston, Massachusetts 02115
T-cells play an important role in controlling viral infections inside the CNS. To study the role of the chemokine receptor CXCR3 in the migration and positioning of virus-specific effector T-cells within the brain, CXCR3-deficient mice were infected intracerebrally with lymphocytic choriomeningitis virus (LCMV). Analysis of the induction phase of the antiviral CD8+ T-cell response did not reveal any immune defects in CXCR3-deficient mice. Yet, when mice were challenged with LCMV intracerebrally, most CXCR3-deficient mice survived the infection, whereas wild-type mice invariably died from CD8+ T-cell-mediated immunopathology. Quantitative analysis of the cellular infiltrate in CSF of infected mice revealed modest, if any, decrease in the number of mononuclear cells recruited to the meninges in the absence of CXCR3. However, immunohistological analysis disclosed a striking impairment of CD8+ T-cells from CXCR3-deficient mice to migrate from the meninges into the outer layers of the brain parenchyma despite similar localization of virus-infected target cells. Reconstitution of CXCR3-deficient mice with wild-type CD8+ T-cells completely restored susceptibility to LCMV-induced meningitis. Thus, taken together, our results strongly point to a critical role for CXCR3 in the positioning of effector T-cells at sites of viral inflammation in the brain.
Key words: viral infection; immunopathology; chemokines; CXCR3; T-cells; knock-out mice
Received Jan 13, 2004; revised April 2, 2004; accepted April 5, 2004.
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