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

TL;DR

CD8 T cells that enter the brain help protect against Zika virus infection and reduce neurological damage.

Contribution

The study reveals that brain-infiltrating CD8 T cells are protective and not exhausted during acute Zika virus infection.

Findings

CD8+ T cells infiltrate the brain during Zika virus infection and show enhanced cytotoxic activity.

Blocking CD8+ T cell infiltration worsens brain inflammation and injury in Zika-infected mice.

PD-1 expression on CD8 T cells indicates activation rather than exhaustion during Zika infection.

Abstract

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.

The online version contains supplementary material available at 10.1038/s41598-026-35079-3.

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