Persistently activated virus-specific CD8 T cells indicate antigen-driven immune aberrations in long COVID
Year: 2026
Type: preprint
Study design: Observational Study
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.
Authors: Mark M. Painter, 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, Amy D. Proal, 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
Institutions: University of Pennsylvania, University of Freiburg, University Medical Center Freiburg, University of California, San Francisco, Orlando College of Osteopathic Medicine, Temple University, University of Florida Health, University of Florida, Yale University, Icahn School of Medicine at Mount Sinai, San Francisco VA Medical Center, Howard Hughes Medical Institute
Language: English
Subfield: Clinical Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7222830723