Sustained antigen-specific CD8+ T cell immunity post-mRNA booster requires notch pathway activation.

Messenger RNA (mRNA) vaccines effectively induce protective immunity, but antigen-specific CD8+ T cell responses exhibit limited persistence. In this study, we aimed to assess CD8+ T cell responses following a third dose of the Pfizer BNT162b2 COVID-19 vaccine and identify factors contributing to their longevity. Using HLA tetramers, we analyzed antigen-specific CD8+ T cells in 141 vaccinated individuals (86.5% female) and identified 2 groups: those with strong responses (strong group) and those with weak responses (weak group) 6 mo after the third mRNA vaccination. Transcriptomic analysis revealed that Notch signaling was upregulated in the strong group, and in vitro, the inhibition of Notch signaling significantly reduced CD8+ T cell expansion. These findings suggest that Notch signaling may contribute to maintain long-term antigen-specific CD8+ T cell responses following mRNA vaccination. Targeting this pathway could offer novel strategies for enhancing vaccine-induced cellular immunity and long-lasting protection.