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Journal of Virology, March 2008, p. 2952-2965, Vol. 82, No. 6
0022-538X/08/$08.00+0     doi:10.1128/JVI.02191-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Regulation of Immune Response and Inflammatory Reactions against Viral Infection by VCAM-1

Rong Ou,^1, Menghua Zhang,^1, Lei Huang,¹ Richard A. Flavell,² Pandelakis A. Koni,^3* and Demetrius Moskophidis^1*

Center for Molecular Chaperones/Radiobiology and Cancer Virology, Medical College of Georgia, Augusta, Georgia 30912,¹ Department of Immunobiology and Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut 06510,² Immunotherapy Center, Medical College of Georgia, Augusta, Georgia 30912³

Received 5 October 2007/ Accepted 21 December 2007

The migration of activated antigen-specific immune cells to the target tissues of virus replication is controlled by the expression of adhesion molecules on the vascular endothelium that bind to ligands on circulating lymphocytes. Here, we demonstrate that the adhesion pathway mediated by vascular cell adhesion molecule 1 (VCAM-1) plays a role in regulating T-cell-mediated inflammation and pathology in nonlymphoid tissues, including the central nervous system (CNS) during viral infection. The ablation of VCAM-1 expression from endothelial and hematopoietic cells using a loxP-Cre recombination strategy had no major effect on the induction or overall tissue distribution of antigen-specific T cells during a systemic infection with lymphocytic choriomeningitis virus (LCMV), except in the case of lung tissue. However, enhanced resistance to lethal LCM and the significantly reduced magnitude and duration of footpad swelling observed in VCAM-1 mutant mice compared to B6 controls suggest a significant role for VCAM-1 in promoting successful local inflammatory reactions associated with efficient viral clearance and even life-threatening immunopathology under particular infection conditions. Interestingly, analysis of the infiltrating populations in the brains of intracerebrally infected mice revealed that VCAM-1 deletion significantly delayed migration into the CNS of antigen-presenting cells (macrophages and dendritic cells), which are critical for optimal stimulation of migrating virus-specific CD8⁺ T cells initiating a pathological cascade. We propose that the impaired migration of these accessory cells in the brain may explain the improved clinical outcome of infection in VCAM-1 mutant mice. Thus, these results underscore the potential role of VCAM-1 in regulating the immune response and inflammatory reactions against viral infections.

Published ahead of print on 23 January 2008.

These authors contributed equally to this work.