Researchers at the University of Pennsylvania have found that a subset of people with long COVID carry persistently activated T cells targeting SARS-CoV-2 and Epstein-Barr virus — evidence that lingering viral antigens may be keeping their immune systems on high alert. The study, posted as a preprint on bioRxiv on October 16, 2026, is among the most detailed immune-profiling efforts in long COVID to date.
According to the PolyBio Research Foundation, which supported the work, the team led by Dr. John Wherry and postdoctoral researcher Dr. Mark Painter analyzed more than 500 blood samples from over 300 individuals, including more than 150 people with long COVID alongside recovered controls and participants sampled during acute COVID-19 or shortly after vaccination. Using laboratory-made HLA tetramers, they identified CD8 T cells recognizing specific viral proteins without first activating them in the lab, preserving evidence of their activity inside the body.
The researchers found that a substantial subgroup of long COVID patients maintained elevated activation of CD8 T cells targeting the SARS-CoV-2 spike protein and Epstein-Barr virus lytic antigens — but not other viral specificities. These spike-specific cells showed gene signatures of chronic stimulation, terminal effector differentiation, and functional exhaustion, and performed poorly when stimulated with matching peptides in the lab.
"This provides key mechanistic insights and identifies a biomarker for stratifying patients, assessing response to treatment, and guiding the development of new therapies," Painter wrote. The collaborators included teams at UCSF, Mount Sinai's Putrino Lab, and Yale immunologist Akiko Iwasaki.
The findings support the viral persistence hypothesis of long COVID and suggest T cells could serve as "biosensors" of hidden antigen reservoirs — potentially helping doctors identify which patients might benefit from antiviral or immune-targeted treatments in future clinical trials.