Brain-infiltrating CD8 T cells retain functional activity to protect against acute Zika virus infection.

Zika virus (ZIKV) infection can cause severe neurological complications, yet the role of CD8+ T cells in controlling viral pathogenesis in the brain remains unclear. Using Ifnar1-/- mice, which lack type I interferon signaling, we demonstrate that ZIKV infection triggers significant infiltration of CD8+ T cells into the brain, accompanied by neurological defects. ZIKV-experienced CD8+ T cells exhibit enhanced cytotoxic potential, and adoptive transfer of these cells improves survival. In contrast, blocking their infiltration exacerbates brain inflammatory and injury-associated signatures, highlighting their protective contribution. Furthermore, PD-1 blockade worsens ZIKV pathology, suggesting that PD-1 expression reflects an activated rather than exhausted state. These findings underscore an important role of infiltrating CD8+ T cells in reducing ZIKV-induced CNS inflammation and suggest that modulating their response could serve as a potential therapeutic strategy for ZIKV-associated neurological disease.