CD4(+) T cells and CD40-CD40L interactions mediate West Nile virus central nervous system clearance and protection from lethal infection

West Nile encephalitis virus (WNV) is a single-stranded positive sense RNA virus that is an important human and veterinary pathogen. Humans, primarily the elderly and immunocompromised, can develop febrile illness, which may progress to encephalitis and death. There is currently no therapy against WNV.; Studies using knockout mouse models have shown that the innate and adaptive immune responses are important in controlling WNV infection. Interferon, complement and other components of the innate immune system help control WNV dissemination early in infection, while adaptive immune responses are critical in clearing infection. Studies in B cell and IgM deficient animals have shown that humoral immune responses are crucial for controlling West Nile virus infection. Antibody responses early in the course of infection limit WNV dissemination and protect animals from death. In addition, CD8+ T cells facilitate efficient clearing of WNV infection from lymphoid tissue and the central nervous system (CNS).; Although these studies have helped define some of the strategies employed by the immune system to limit WNV infection, the role of CD4+ T lymphocytes in controlling WNV, and flaviviral infections in general, is still poorly understood. CD4+ T cells prime adaptive immune responses, but their role in controlling humoral and cell-mediated responses during primary viral infections remains controversial. For some viruses, CD4 + T cell help is only required to prime memory responses whereas for others it is essential for an effective primary response. CD40 is a costimulatory molecule whose ligand, CD40L, is primarily found on activated CD4+ T cells. Interaction of CD40 with its ligand enhances B cell and CD8+ T cell responses to T-dependent antigens, although this is also virus-specific.; Using mouse models with genetic and acquired deficiency of CD4, we show herein that the dominant protective role of CD4+ T cells during primary WNV infection is to provide help for antibody responses and sustain WNV-specific CD8+ T cell responses in the CNS thereby enabling viral clearance. In addition we have utilized CD40-deficient mice to determine that T-dependent responses are critical for induction of WNV-specific antibody responses leukocyte trafficking to the CNS and migration into the parenchyma. In contrast, neither CD4+ T cells nor CD40-CD40L interactions are required for the initial priming of CD4+ and CD8 + T cells during primary WNV infection.