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-α/βR−/− mice. Depletion of CD8+ T cells from IFN-α/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-α/βR−/− mice. DENV-specific CD8+ T cells produced IFN-γ, TNF-α, 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.

Variation in Inflammatory/Regulatory Cytokines in Secondary, Tertiary, and Quaternary Challenges with Dengue Virus

“…There are recent reports that confirm the importance of cellmediated response in conferring protective response against dengue virus. 77,78 This is the first report of cytokine expression after a quaternary dengue challenge, and supports the importance of heterovalent immunity to achieve a successful dengue vaccine.…”

Dengue vaccine–induced CD8+ T cell immunity confers protection in the context of enhancing, interfering maternal antibodies

“…This has led the dengue scientific community to consider the role of T cells in protection against DENV. Recent evidence from mouse and human studies suggests indeed that T cells, particularly the CD8 + subset, may be important mediators of protection (17)(18)(19)(20)(21)(22). Greater appreciation of the importance of T cells is also evident from recent vaccine developments that focus on the assessment of T cell activity in vaccinated individuals and animals (23)(24)(25)(26).…”

“…We also demonstrated that maternal antibodies inhibit seroconversion upon PDK53 vaccination in pups born to PDK53-immune dams. However, we hypothesized that vaccination of these pups with PDK53 may still induce T cell-mediated protection, which usually targets the more conserved nonstructural proteins (17,18,38,39). It was indeed reported that the T cell response to vaccination was not impaired by maternal antibodies (29).…”

Dengue Virus: Host-Pathogen Interactions and Emerging Role of DNA Vaccines

“…The infection of B cells and fibroblasts at in vitro level are known but at in-vivo it is still a question mark [74]. Based on these observations, it might be possible that multiple cell types which include macrophages, dendritic cells and hepatocytes are the cells that are responsible for enhancing dengue virus infection [75].…”