Persistently activated virus-specific CD8 T cells indicate antigen-driven immune aberrations in long COVID

Painter, M. M.; Reeg, D. B.; Douek, N. R.; Gray-Gaillard, S. L.; Manne, S.; Giles, J. R.; Dalhuisen, T.; Buitrago, M.; Fehrman, E. A.; Ryder, D.; Williams, M. C.; Rybicki, A.-K.; Baraniecki-Zwil, G.; Ahn, Z.; Reilly, J. P.; Sandsmark, D. K.; Harhay, M. O.; Tabachnikova, S.; Bhattacharjee, B.; Putrino, D.; Kelly, J. D.; Martin, J. N.; Abramoff, B. A.; Meyer, N. J.; Iwasaki, A.; Henrich, T. J.; Deeks, S. G.; Peluso, M. J.; Wherry, E. J.

doi:10.64898/2026.10.14.759221

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bioRxiv · 10.64898/2026.10.14.759221

Persistently activated virus-specific CD8 T cells indicate antigen-driven immune aberrations in long COVID

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Abstract

Long COVID (LC) affects millions of people worldwide, yet its driving mechanisms remain incompletely defined and no treatment has been approved. Persistence of SARS-CoV-2 and reactivation of herpesviruses have been implicated in LC, but direct detection of these viral antigens in blood and tissues has been challenging. T cells are exquisitely sensitive to viral antigens, survey organs throughout the body, and can be readily sampled in peripheral blood. Using high-dimensional spectral flow cytometry and single-cell sequencing approaches with multiplexed peptide/HLA tetramers, we profiled virus-specific T cells from hundreds of people with LC and recovered controls. We identified a subset of people with LC that maintained elevated activation of CD8 T cells targeting SARS-CoV-2 spike and/or lytic antigens from Epstein-Barr virus, but not other viral specificities. Spike-specific cells in LC expressed genes linked to TCR stimulation, terminal effector differentiation, and exhaustion and demonstrated reduced functionality upon cognate peptide stimulation ex vivo. Thus, T cells from a subset of people with LC are likely chronically stimulated by persistent SARS-CoV-2 antigens. These findings establish the use of T cells as biosensors of persisting antigen in LC and other disease settings and may help develop new therapeutic strategies for LC.

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Painter, M. M., Reeg, D. B., Douek, N. R., Gray-Gaillard, S. L., Manne, S., Giles, J. R., Dalhuisen, T., Buitrago, M., Fehrman, E. A., Ryder, D., Williams, M. C., Rybicki, A.-K., Baraniecki-Zwil, G., Ahn, Z., Reilly, J. P., Sandsmark, D. K., Harhay, M. O., Tabachnikova, S., Bhattacharjee, B., Putrino, D., Kelly, J. D., Martin, J. N., Abramoff, B. A., Meyer, N. J., Iwasaki, A., Henrich, T. J., Deeks, S. G., Peluso, M. J., Wherry, E. J.. 2026-10-16. Persistently activated virus-specific CD8 T cells indicate antigen-driven immune aberrations in long COVID. https://doi.org/10.64898/2026.10.14.759221

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