Cross-Reactive Memory CD4 + T Cells Alter the CD8 + T-Cell Response to Heterologous Secondary Dengue Virus Infections in Mice in a Sequence-Specific Manner

Secondary dengue virus (DENV) infection is a major factor contributing to the risk for severe disease, an effect that depends upon the sequence of infection with different DENV serotypes. We previously reported sequence-dependent effects of secondary DENV infection on CD8⁺ T-cell responses in mice. To further evaluate the effect of infection sequence, we analyzed DENV-specific CD4⁺ T-cell responses and their relationship to the CD8⁺ T-cell response. Serotype cross-reactivity of CD4⁺ T-cell responses also depended upon the sequence of serotypes in this model. Furthermore, adoptive transfer of memory CD4⁺ T cells altered the response of memory CD8⁺ T cells to secondary infection. These data demonstrate the interaction of different components of the T-cell response in determining the immunological outcome of secondary DENV infection.