CD4+ T Cells Are Not Required for the Induction of Dengue Virus-Specific CD8+ T Cell or Antibody Responses but Contribute to Protection after Vaccination

Abstract

The contribution of T cells to the host response to dengue virus (DENV) infection is not well understood. We previously demonstrated a protective role for CD8⁺ T cells during primary DENV infection using a mouse-passaged DENV strain and IFN-α/βR^−/− C57BL/6 mice, which are susceptible to DENV infection. In this study, we examine the role of CD4⁺ T cells during primary DENV infection. Four I-A^b–restricted epitopes derived from three of the nonstructural DENV proteins were identified. CD4⁺ T cells expanded and were activated after DENV infection, with peak activation occurring on day 7. The DENV-specific CD4⁺ T cells expressed intracellular IFN-γ, TNF, IL-2, and CD40L, and killed peptide-pulsed target cells in vivo. Surprisingly, depletion of CD4⁺ T cells before DENV infection had no effect on viral loads. Consistent with this observation, CD4⁺ T cell depletion did not affect the DENV-specific IgG or IgM Ab titers or their neutralizing activity, or the DENV-specific CD8⁺ T cell response. However, immunization with the CD4⁺ T cell epitopes before infection resulted in significantly lower viral loads. Thus, we conclude that whereas CD4⁺ T cells are not required for controlling primary DENV infection, their induction by immunization can contribute to viral clearance. These findings suggest inducing anti-DENV CD4⁺ T cell responses by vaccination may be beneficial.