title: A protective role for dengue virus-specific CD8+ T cells.
abstract: Infection with one of the four serotypes of dengue virus (DENV1-4) can result in a range of clinical manifestations in humans, from dengue fever to the more serious dengue hemorrhagic fever/dengue shock syndrome. Although T cells have been implicated in the immunopathogenesis of secondary infections with heterologous DENV serotypes, the role of T cells in protection against DENV is unknown. In this study, we used a mouse-passaged DENV2 strain, S221, to investigate the role of CD8(+) T cells in the immune response to primary DENV infection. S221 did not replicate well in wild-type mice, but did induce a CD8(+) T cell response, whereas viral replication and a robust CD8(+) T cell response were observed after infection of IFN-alpha/betaR(-/-) mice. Depletion of CD8(+) T cells from IFN-alpha/betaR(-/-) mice before infection resulted in significantly higher viral loads compared with undepleted mice. Mapping the specificity of the CD8(+) T cell response led to the identification of 12 epitopes derived from 6 of the 10 DENV proteins, with a similar immunodominance hierarchy observed in wild-type and IFN-alpha/betaR(-/-) mice. DENV-specific CD8(+) T cells produced IFN-gamma, TNF-alpha, expressed cell surface CD107a, and exhibited cytotoxic activity in vivo. Finally, immunization with four of the immunodominant CD8(+) T cell epitopes enhanced viral clearance. Collectively, our results reveal an important role for CD8(+) T cells in the host defense against DENV and demonstrate that the anti-DENV CD8(+) T cell response can be enhanced by immunization, providing rationale for designing DENV-specific vaccines that induce cell-mediated immunity.
authors.affiliation: Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA.
authors.forename: Lauren E
authors.initials: LE
authors.lastname: Yauch
authors.forename: Raphaël M
authors.initials: RM
authors.lastname: Zellweger
authors.forename: Maya F
authors.initials: MF
authors.lastname: Kotturi
authors.forename: Afrina
authors.initials: A
authors.lastname: Qutubuddin
authors.forename: John
authors.initials: J
authors.lastname: Sidney
authors.forename: Bjoern
authors.initials: B
authors.lastname: Peters
authors.forename: Tyler R
authors.initials: TR
authors.lastname: Prestwood
authors.forename: Alessandro
authors.initials: A
authors.lastname: Sette
authors.forename: Sujan
authors.initials: S
authors.lastname: Shresta