Why the coronavirus can infect us without making us sick

In the summer of 2020, Antonio Bertoletti, a virologist at Duke-NUS Medical School in Singapore, had one such opportunity to study asymptomatic COVID-19 patients. Although Singapore had so far largely controlled the spread of COVID-19, an outbreak was raging among its migrant workers, many of whom were from India and Bangladesh. To contain the outbreak, the government paid the workers to isolate at home and track their symptoms with thermometers and oximeters. During the isolation period, Bertoletti and his colleagues recruited 478 workers who were willing to have their immune responses tracked through periodic blood samples. Over a six-week period, about a third of the study participants caught and recovered from COVID-19. A large majority of cases were asymptomatic, and the rest were mostly mild.

Bertoletti and his colleagues were interested in virus-specific T cells that are essential to the adaptive-immune response. When they isolated these cells from blood samples, they found that asymptomatic patients had more specific and coordinated T-cell responses with high levels of an antiviral molecule and another that regulates other T cells. Their adaptive immunity looked more “fit,” Bertoletti told me. The sicker patients’ cells released a broader range of inflammatory molecules, suggesting that their immune response was less targeted.

Although COVID-19 antibodies got a lot of attention early in the pandemic, T cells are now emerging as key to fighting COVID-19. Patients can recover from COVID-19 without antibodies at all—as long as they have T cells to fight the virus. T cells may play an additional role in milder infections: Depending on where in the world you look, some 28 to 50 percent of people have T cells that predate the pandemic but nevertheless react to the new virus. These T cells may be remnants of infections with related coronaviruses, a theory supported by one study, which found that people who were more recently infected by other coronaviruses tended to have milder COVID-19 infections. In Singapore, 93 percent of the cases Bertoletti found were asymptomatic—a much higher percentage than in other closed settings, such as cruise ships—a result he attributes to the migrant workers’ relative youth and possible cross-reactive T cells, which seem to be more common in some parts of the world than in others. To further understand the role of cross-reactive T cells, Sette, at La Jolla, is studying whether patients who possess them also mount a stronger immune response after receiving a COVID-19 vaccine.