ABOVE: An artist's interpretation of a T cell targeting SARS-CoV-2

In May, researchers showed that people with mild forms of COVID-19, the disease caused by the SARS-CoV-2 virus, have circulating T cells that respond to the virus. Now, in a Science Immunology study published last week (June 26), a collaborating research team has determined that people who are sick enough with COVID-19 to be hospitalized in the intensive care unit also make SARS-CoV-2-reactive T cells. In both studies, the researchers found that a subset of healthy, unexposed people also had some of these T cells that react to the virus, perhaps due to previous exposures to other coronaviruses that cause symptoms of the common cold.

The latest study provides more solid evidence that there are SARS-CoV-2-specific T cells that are induced by the infection, says Antonio Bertoletti, who studies T cells at Duke-NUS...

Rory de Vries, a virologist and immunologist at Erasmus University Medical Center in the Netherlands, was visiting immunologist Alessandro Sette’s lab at the La Jolla Institute for Immunology in California to collaborate on another project when “all hell broke loose” with the pandemic, Sette tells The Scientist. Sette’s group had been developing tools to investigate adaptive immunity to SARS-CoV-2, but in California at that point, they didn’t have a COVID-19 patient population to try them in. As de Vries prepared to return home in March, Europe already had confirmed cases of SARS-CoV-2, so he took the tools the team had developed back to the Netherlands.

de Vries and colleagues collected blood from 10 COVID-19 patients—four women and six men admitted to the intensive care unit with acute respiratory distress syndrome requiring ventilation—and 10 healthy volunteers. The team exposed the study participants’ immune cells to a pool of predicted SARS-CoV-2 peptides in vitro to see whether or not the cells would react.

The team determined that all of the ill patients had fewer overall T cells than the healthy volunteers, which was consistent with earlier findings from other groups. All patients had helper T cells and eight of 10 had killer T cells that targeted SARS-CoV-2 proteins. These reactive T cells showed up within about 10 days of symptom onset in the patients. The strongest responses were to the SARS-CoV-2 spike protein, but cells responded to membrane and nuclear viral proteins, too.

“The frequency of these corona-specific T cells in these patients . . . is at least at the same level, if not higher than I see in other viruses,” says Nina Babel, an immunologist at Charité – Universitätsmedizin Berlin who did not participate in the study. This indicates that the lack of T-cell response is probably not the problem in these patients, she explains.

The study authors reported that two healthy controls also had circulating SARS-CoV-2-fighting T cells, something that showed up in healthy controls in the study of milder cases of COVID-19 in May. “A likely explanation is that this is reflective of exposure to common cold coronaviruses which . . . are cousins of SARS-CoV-2,” Sette says. This could give the immune system a head start by allowing it to leverage preexisting reactivity to mount a faster or better response, or it might be a disadvantage in that preexisting immunity could lead the immune system to take SARS-CoV-2 less seriously, he adds. While Sette thinks the second idea is less likely, he acknowledges that the jury is still out about the role this reactivity in unexposed people, which has also been shown in studies from other groups, plays in the severity of COVID-19.

The most curious thing “is this issue of cells that recognize SARS-CoV-2 from people who’ve never seen the virus,” says Stanley Perlman, an immunologist at the University of Iowa who was not involved in the study. His group has done work with MERS-CoV—the coronavirus responsible for Middle East Respiratory Syndrome—and they see almost no evidence of this kind of preexisting immunity, he says. The authors “postulate that this [cross-reactivity] comes from circulating coronaviruses or something else. It would be interesting to show what that something else is.”

Understanding the immune response to SARS-CoV-2 will help researchers determine what aspects of that response they can leverage and which aspects make people sicker and are to be avoided, de Vries tells The Scientist. “The next steps would then of course be treatment, but especially vaccinations,” he explains. “If we vaccinate people and direct the immune response, we need to know what immunity we want to induce and what immunity we want to stay away from.”

D. Weiskopf et al., “Phenotype and kinetics of SARS-CoV-2-specific T cells in COVID-19 patients with acute respiratory distress syndrome,” Science Immunologydoi:10.1126/sciimmunol.abd2071, 2020.

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