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Journal of Virology, September 2007, p. 9801-9811, Vol. 81, No. 18
0022-538X/07/$08.00+0     doi:10.1128/JVI.00941-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

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

Elizabeth Sitati,1 Erin E. McCandless,2 Robyn S. Klein,2,3,4 and Michael S. Diamond1,2,3*

Departments of Molecular Microbiology,1 Pathology and Immunology,2 Medicine,3 Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, Missouri 631104

Received 2 May 2007/ Accepted 22 June 2007

Recent studies have established a protective role for T cells during primary West Nile virus (WNV) infection. Binding of CD40 by CD40 ligand (CD40L) on activated CD4+ T cells provides an important costimulatory signal for immunoglobulin class switching, antibody affinity maturation, and priming of CD8+ T-cell responses. We examined here 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 immunoglobulin M (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 central nervous system (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.

* Corresponding author. Mailing address: Departments of Medicine, Molecular Microbiology, and Pathology and Immunology, Washington University School of Medicine, 660 South Euclid Ave., Box 8051, St. Louis, MO 63110. Phone: (314) 362-2842. Fax: (314) 362-9230. E-mail: diamond{at}borcim.wustl.edu

{triangledown} Published ahead of print on 11 July 2007.

Journal of Virology, September 2007, p. 9801-9811, Vol. 81, No. 18
0022-538X/07/$08.00+0     doi:10.1128/JVI.00941-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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