Persistently activated virus-specific CD8 T cells indicate antigen-driven immune aberrations in long COVID
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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BibTeX
@misc{painter2026persistently,
title = {{Persistently activated virus-specific CD8 T cells indicate antigen-driven immune aberrations in long COVID}},
author = {Mark M. Painter and David B. Reeg and Naomi R. Douek and Sophie L. Gray-Gaillard and Sasikanth Manne and Josephine R. Giles and Thomas Dalhuisen and Melissa Buitrago and Emily A. Fehrman and Dylan Ryder and Meghann C. Williams and Ava-Kathleen Rybicki and Gwen Baraniecki-Zwil and Zina Ahn and John P. Reilly and Danielle K. Sandsmark and Michael O. Harhay and Sasha Tabachnikova and Bornali Bhattacharjee and David Putrino and Amy D. Proal and J. Daniel Kelly and Jeffrey N. Martin and Benjamin A. Abramoff and Nuala J. Meyer and Akiko Iwasaki and Timothy J. Henrich and Steven G. Deeks and Michael J. Peluso and E. John Wherry},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.14.759221},
url = {https://www.biorxiv.org/content/10.64898/2026.10.14.759221v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Persistently activated virus-specific CD8 T cells indicate antigen-driven immune aberrations in long COVID
AU - Mark M. Painter
AU - David B. Reeg
AU - Naomi R. Douek
AU - Sophie L. Gray-Gaillard
AU - Sasikanth Manne
AU - Josephine R. Giles
AU - Thomas Dalhuisen
AU - Melissa Buitrago
AU - Emily A. Fehrman
AU - Dylan Ryder
AU - Meghann C. Williams
AU - Ava-Kathleen Rybicki
AU - Gwen Baraniecki-Zwil
AU - Zina Ahn
AU - John P. Reilly
AU - Danielle K. Sandsmark
AU - Michael O. Harhay
AU - Sasha Tabachnikova
AU - Bornali Bhattacharjee
AU - David Putrino
AU - Amy D. Proal
AU - J. Daniel Kelly
AU - Jeffrey N. Martin
AU - Benjamin A. Abramoff
AU - Nuala J. Meyer
AU - Akiko Iwasaki
AU - Timothy J. Henrich
AU - Steven G. Deeks
AU - Michael J. Peluso
AU - E. John Wherry
PY - 2026
DA - 2026/10/14
PB - bioRxiv
DO - 10.64898/2026.10.14.759221
UR - https://www.biorxiv.org/content/10.64898/2026.10.14.759221v1
AB - 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.
SN - 2692-8205
ER -