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

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.

Published ahead of print on 11 July 2007.