New Results
, David B. Reeg, Naomi R. Douek, Sophie L. Gray-Gaillard, Sasikanth Manne, Josephine R. Giles, Thomas Dalhuisen, Melissa Buitrago, Emily A. Fehrman, Dylan Ryder, Meghann C. Williams, Ava-Kathleen Rybicki, Gwen Baraniecki-Zwil, Zina Ahn, John P. Reilly, Danielle K. Sandsmark, Michael O. Harhay, Sasha Tabachnikova, Bornali Bhattacharjee, David Putrino, J. Daniel Kelly, Jeffrey N. Martin, Benjamin A. Abramoff, Nuala J. Meyer, Akiko Iwasaki, Timothy J. Henrich, Steven G. Deeks, Michael J. Peluso, E. John Wherry
doi: https://doi.org/10.64898/2026.10.14.759221
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.
Competing Interest Statement
EJW is an advisor for Absci, Arpelos Bio, Arsenal Biosciences, Coherus, IpiNovyx, Jazz Pharma, New Limit, Marengo, and Santa AnaBio. EJW is a founder of Arpelos Bio, Arsenal Biosciences, and holds stock in Coherus. JRG is a consultant for Arsenal Biosciences, Cellanome, Seismic Therapeutics and ActusBio. BAA is a consultant for Pfizer. The authors declare no additional conflicts of interest.
Funder Information Declared
Polybio Research Foundation
National Institutes of Health, F32AI181343, K99AI187316, R01AI155577, P01AI117950, P01AI108545, U19AI082630
National Institutes of Health, https://ror.org/01cwqze88, R35HL161196
Colton Center for Autoimmunity
Parker Institute for Cancer Immunotherapy, https://ror.org/0184qbg02
Roberts Family Katalin Karikó Fellowship in Vaccine Development
Steven & Alexandra Cohen Foundation, https://ror.org/04ns7ha44
Boehringer Ingelheim (Germany), https://ror.org/00q32j219
Copyright
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.