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Fred Hutchinson Cancer Center

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Cell Rep. Med., Jul 29 2026, S2666-3791(26)00363-0 | https://doi.org/10.1016/j.xcrm.2026.102946 Persistent cytolytic CD8+ T cells recognize SARS-CoV-2 and herpesvirus epitopes in long COVID

Tongcui Ma,^1,2,9 Heeju Ryu,^3,9 Kailin Yin,^1,2 Thomas Dalhuisen,⁴ Douglas Robbins,⁴ Tyrine T. Bailey,⁴ Sean A. Thomas,⁴
Emily A. Fehrman,⁴ J. Daniel Kelly,⁵ Jeffrey N. Martin,⁵ Kara L. Lynch,⁶ Sulggi A. Lee,⁷ Steven G. Deeks,⁴
Timothy J. Henrich,⁸ Michael J. Peluso,⁴ Evan W. Newell,^3,* and Nadia R. Roan,^1,2,*

¹Gladstone Institutes, University of California, San Francisco, San Francisco, CA, USA
²Department of Urology, University of California, San Francisco, San Francisco, CA, USA
³Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, USA
⁴Division of HIV, Infectious Diseases, and Global Medicine, University of California, San Francisco, San Francisco, CA, USA
⁵Department of Medicine, San Francisco VA Medical Center, University of California, San Francisco, San Francisco, CA, USA
⁶Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA, USA
⁷Zuckerberg San Francisco General Hospital and the University of California, San Francisco, San Francisco, CA, USA
⁸Division of Experimental Medicine, University of California, San Francisco, San Francisco, CA, USA
⁹These authors contributed equally

^*Correspondence: Evan W. Newell, Nadia R. Roan

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 those for cytomegalovirus (CMV) and Epstein-Barr virus (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 T central memory cell (Tcm)- instead of terminally differentiated memory T cell (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.

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