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

La Crosse virus (LACV) is a leading cause of pediatric encephalitis in the US, with no approved vaccines or antivirals. Weanling mice (3 weeks old) are highly susceptible to lethal LACV infection, whereas adult mice (≥8 weeks old) are resistant. Here, we show that adult mice generate robust, polyfunctional CD4 and CD8 T cell responses targeting LACV structural and non-structural proteins, with high production of IFN-γ, granzyme B, IL-2, and TNF-α. These T cells display strong cytotoxicity against cells pulsed with Gc and N antigens. In contrast, weanlings mount weak T cell responses and exhibit 100% mortality by 7 days post-infection. Immunization of weanling mice with LFn-LACV-Gc or -N enhanced cytotoxic T cell activity, reduced brain viral loads, and significantly improved survival, highlighting their potential as vaccine candidates. Our study identifies age-dependent T cell responses as key correlates of protection and supports vaccine development against LACV-induced pediatric encephalitis.