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J. Virol. doi:10.1128/JVI.00941-07
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

CD40-CD40 Ligand Interactions Promote Trafficking of CD8⁺ T Cells into the Brain and Protection against West Nile Virus Encephalitis

Departments of Molecular Microbiology, Pathology & Immunology, Medicine, and Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, MO 63110

^* To whom correspondence should be addressed. Email: diamond{at}borcim.wustl.edu.

	Abstract

Recent studies have established a protective role for T cells during primary West Nile virus infection. Binding of CD40 by CD40 ligand (CD40L) on activated CD4⁺ T cells provides an important co-stimulatory signal for immunoglobulin class switching, antibody affinity maturation, and priming of CD8⁺ T cell responses. Herein, we examined the function of CD40-dependent interactions in limiting primary WNV infection. Compared to congenic wild type mice, CD40^-/- mice uniformly succumbed to WNV infection. Although CD40^-/- mice produced low levels of WNV-specific IgM and IgG, viral clearance from the spleen and serum was not altered and CD8⁺ T cell priming in peripheral lymphoid tissues was normal. Unexpectedly, CD8⁺ T cell trafficking to the CNS was markedly impaired in CD40^-/- mice, and this correlated with elevated WNV titers in the CNS and death. In the brains of CD40^-/- mice, T cells were retained in the perivascular space and did not migrate into the parenchyma, the predominant site of WNV infection. In contrast, in wild type mice, T cells trafficked to the site of infection in neurons. Beside its role in maturation of antibody responses, our experiments suggest a novel function of CD40-CD40L interactions: to facilitate T cell migration across the blood-brain barrier to control WNV infection.

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