Tonto, P. B.; Gallon, S.; Alatrash, R.; Wang, W.-K.; Herrera, B. B.

Widespread yellow fever virus (YFV) immunity in Sub-Saharan Africa may mitigate orthoflavivirus outbreaks. Here, we investigate whether pre-existing YFV-17D immunity confers cross-protection against dengue virus serotype 2 (DENV-2) in a murine model. IFNAR1-/- mice immunized with YFV-17D exhibited significantly reduced DENV-2 viremia, weight loss, and disease severity, with improved survival compared to YFV-naive controls. Mechanistic studies revealed that cross-protection was mediated by heterologous T cell responses rather than cross-neutralizing antibodies. Depletion of T cells in YFV-17D-immune mice prior to DENV-2 challenge resulted in increased viremia, weight loss, and disease severity, underscoring the protective role of YFV-17D-elicited T cell immunity. Furthermore, YFV-17D-specific T cells displayed cytotoxicity against DENV NS3- and NS5-pulsed cells, demonstrating their functional role in viral control. These findings highlight the critical contribution of heterologous T cell immunity in YFV-17D-mediated protection against DENV-2 and suggest that vaccines designed to elicit T cell responses could enhance cross-protection against orthoflavivirus infections.