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A Protective Role for Dengue Virus-Specific CD8⁺ T Cells ¹

Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037

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-/βR^–/– mice. Depletion of CD8⁺ T cells from IFN-/βR^–/– 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-/βR^–/– mice. DENV-specific CD8⁺ T cells produced IFN-, TNF-, 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This study was supported by National Institutes of Health Grants AI060989 and AI077099-01 (to S.S.), by a developmental project award from the Pacific Southwest Regional Center of Excellence (U54 AI065359 to S.S.), and by fellowships from the Center for Infectious Diseases and the Diabetes & Immune Disease National Research Institute (to L.E.Y.). This is Kirin publication no. 1027.

² Address correspondence and reprint requests to Dr. Sujan Shresta, Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, 9420 Athena Circle, La Jolla, CA 92037. E-mail address: sujan{at}liai.org

³ Abbreviations used in this paper: DENV, dengue virus; DF, dengue fever; DHF, dengue hemorrhagic fever; DSS, dengue shock syndrome; GE, genomic equivalent; SFC, spot-forming cell; LCMV, lymphocytic choriomeningitis virus; ICS, intracellular cytokine staining; VACV, vaccinia virus.

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