While antibodies have been the focus of testing for past infection with COVID-19, T cells will also provide some insights -- potentially better ones, experts say.
These lymphocytes are the first responders that then coordinate the immune response while building an imprint, a memory, so that subsequent infections fade quickly, often unnoticed.
T cell tests are more complex and typically reserved for research, but some may be coming to the clinic soon, with at least one company seeking FDA emergency use authorization (EUA). Recent studies indicate that assaying T cells can even improve diagnostic accuracy and possibly predict how COVID-19 will unfold.
"Testing T cell responses can accelerate detection of an infection by as much as a week. The cells come in on day 2 and they divide very quickly, to detectable levels as early as 3 or 4 days from infection," said Dawn Jelley-Gibbs, PhD, who investigated T cells in influenza at the Trudeau Institute in Saranac Lake, New York.
"Identifying people who have been infected and become immune could have huge benefits for enabling society to safely return to normalcy. Numerous antibody tests exist, but doubts remain about their reliability and about antibody longevity post-infection," said Maria Oliver, PhD, senior scientist at Indoor Biotechnologies in Great Britain, one of several companies developing clinical T cell tests.
T Cell Basics
T cells descend from stem cells in the bone marrow. During development, they migrate to the thymus gland (hence the "T"), where they display antigens that are whittled down to those that recognize self. Antigens distinguish subtypes: CD4 T cells ("helpers") recognize foreign antigens on macrophages, stimulate B cells to produce antibodies, secrete cytokines, and activate CD8 T cells ("cytotoxic"). CD8 T cells burst virally-infected cells.
T cell receptors (TCRs) are astonishingly diverse. Researchers have assessed TCR diversity using binding to varied quartets ("tetramers") of the MHC peptides that macrophages display. , an open database from Adaptive Biotechnologies and Microsoft, is nearing 2 billion sequenced TCRs, requiring a machine-learning approach to distinguish them.
The good news is that in COVID-19, T cells appear a day or two after symptoms start, bind the virus at several sites, and persist – so far.
Researchers from the University of Freiburg in Germany tracked CD8 T cells in 26 convalescing patients for 100 days and .
"Since we did not observe a substantial decline during the follow-up, we assume that the memory CD8 T cell response remains sustained for a longer period, more than a year. But only longitudinal studies over a long time will prove this assumption right or wrong," said corresponding author Christoph Neumann-Haefelin, MD.
Many researchers hope that a T cell response will mirror that for SARS and MERS: 2 to 10 years.
A Brief History of T Cells in COVID-19
T cells have been slow to appear on the COVID testing landscape because they're challenging to work with; protocols vary and standardization is difficult. A literature labyrinth on T cells in COVID expanded in the middle of the summer as a slew of preprints evolved into published papers:
- Alba Grifoni, PhD, and colleagues on June 25 that identifying T cell responses can provide insights into the pathogenesis and rise of immunity, inform vaccine development, and refine public health measures.
- Daniel Altmann, PhD, and Rosemary Boyton, MD, on July 17 about the function, durability, and protection of SARS-CoV-2-specific T cells.
- Julian Braun, PhD, and co-authors identified CD4 T cells specific to both ends of the viral spike protein in COVID patients and cells specific to one end of the spike in seronegative healthy donors, who may have retained some immunity from exposure to past coronaviruses. Their on July 29.
- The UPenn COVID Processing Unit described three "immunotypes with therapeutic implications" on September 4. The team is developing an assay that can be "certified for clinical use, as well as test whether immunotypes respond differently to specific therapies," explained co-author Nuala Meyer, MD.
Essentially, this literature suggests that the naturally-induced T cell response begins early in infection and provides immunity for at least 6 months.
That could mean T cell tests will not only identify a robust immune response in infected individuals, but may also be helpful in tracking long-term response to a vaccine.
The First Clinical T Cell Test for COVID
Adaptive Biotechnologies is developing T-Detect COVID and plans to file for an EUA before year's end. A study of 2,900 people in Vo, near Padua, Italy, inspired the test. That's where the first Italian died from COVID-19, on February 21. A two-week lockdown ensued.
Citizens were PCR-tested at the start and end of lockdown. Sixty days later, antibody serology and T cell testing were done on 70 of the 81 patients who tested positive.
T-cell testing identified 68 of 70 (97%) of the infections; antibody serology found 54 (77%). Of the 70 people, 24 had no symptoms. In addition, the T cell test identified 45 of 2,220 citizens who'd had negative PCR tests, about half of whom had reported symptoms or contact with someone testing positive.
The new test will initially be used to detect past infection, said Adaptive's chief medical officer, Lance Baldo, MD, but it may also be prognostic, because the degree of T cell response correlated to symptoms and severity, but antibody response didn't.
The machine learning contrasted degree of illness – asymptomatic, symptomatic, hospitalized -- with T cell receptor diversity and number, what Baldo called breadth and depth. "That yields a score. The higher the score, the more likely you are to have been very sick. So a T cell score might be able to predict whether outcome will be good or bad." Those findings were last week.
The unprecedented outpouring of research findings on COVID-19 is building an armamentarium of diagnostic tests, treatments, and vaccines. "Every one of these assays -- serology for antibodies, T cell tests -- has a role to play," Baldo said, "and figuring out how to use them is important to a practicing clinician."