Immunodominant structural proteins Gc and N drive T cell-mediated protection against La Crosse virus

La Crosse virus (LACV) is a major cause of pediatric encephalitis in the U.S., primarily affecting children under 16 years. Despite severe morbidity and potential mortality risks, no vaccines or antivirals exist. Murine models recapitulate human susceptibility patterns, with weanling mice (3 weeks old) succumbing to disease while adults ([≥]8 weeks old) exhibit resistance. We characterized the T cell responses underlying this difference. Adult mice mounted robust CD4+ and CD8+ T cell responses by 6 days post-infection (dpi), with sustained IFN-{gamma}, granzyme B, IL-2, and TNF- production. These T cells expanded significantly and exhibited in vivo cytotoxicity against cells pulsed with LACV glycoprotein (Gc) and nucleocapsid (N) antigens. In contrast, weanlings showed weak T cell responses and 100% mortality by 7 dpi. Immunization with LFn-LACV-Gc and -N improved T cell cytotoxicity and survival in weanlings, highlighting their potential as vaccines. These findings inform strategies to mitigate LACV-induced encephalitis in children.