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Dryad

Persistent cytolytic CD8+ T cells recognize SARS-CoV-2 and herpesvirus epitopes in Long COVID

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Jun 19, 2026 version files 759.12 MB

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Abstract

Viral-specific CD8+ T cells play roles in protective immunity and immunopathology including during COVID-19. Leveraging combinatorial tetramers, we profiled CD8+ T cells specific for SARS-CoV-2, as well as CMV and EBV – herpesviruses implicated in COVID-19 pathogenesis. During severe COVID-19, EBV-specific CD8+ T cells exhibit a stem-like state whereas CMV-specific ones are terminally differentiated and cytolytic. Comparing post-acute samples from Long COVID (LC) individuals to those recovered revealed that LC-associated CMV-specific CD8+ T cells are Tcm- instead of Temra-biased. In LC individuals, CD8+ T cells specific for SARS-CoV-2, CMV, and EBV are preferentially terminally differentiated, exhausted, and cytolytic. Cytolytic granzyme B-expressing CD8+ T cells are particularly prominent among LC women. As granzyme B is upregulated on viral-specific CD8+ T cells during acute viremia, an inability to shut down COVID-19-induced cytolytic effector expression may drive preferential persistence of cytolytic CD8+ T cells in people with LC which may contribute to LC pathogenesis.