Scientists discover T cell characteristics that predict recovery from severe COVID-19

While vaccines do a remarkable job of slowing the COVID-19 pandemic, those infected can still die from serious illness and new drugs to treat them have been slow to emerge. What kills these patients in the end does not appear to be the virus itself, but an overreaction of their immune system that results in massive inflammation and tissue damage.

By studying a type of immune cell called T cells, a team of scientists from Gladstone have discovered fundamental differences between patients who overcome severe COVID-19 and those who succumb to it. The team, working with researchers at UC San Francisco and Emory University, also found that dying patients harbor relatively large numbers of T cells capable of infiltrating the lungs, which may contribute to the extensive lung deterioration that is a hallmark of deadly COVID-19. .

The results, published in the scientific journal Cell reports, could pave the way for new treatments. Currently, patients hospitalized with severe COVID-19 are primarily given dexamethasone, a drug used to reduce inflammation.

“Dexamethasone has saved the lives of many patients,” said Gladstone associate researcher Nadia Roan, PhD, lead author and study correspondent. “But that’s not always enough. Our study suggests that it may also be beneficial to directly prevent excess immune cells, including inflammatory T cells, from entering the lungs and causing further damage. . This approach could be a good adjunct to anti-inflammatory treatments for COVID-19 patients in the intensive care unit. “

Labor could also help in the prognosis of the disease.

“Some patients can become seriously ill from the virus,” says Warner Greene, MD, PhD, senior investigator at Gladstone and co-lead author of the study. “We urgently need effective means to anticipate the course of the disease, as well as to alleviate lung damage in people with severe COVID-19. “

T cell imbalance

T cells are a crucial part of a successful immune response to many viruses, including SARS-CoV-2, the virus that causes COVID-19. And they are markedly depleted in the blood during severe COVID-19.

To characterize the characteristics of the remaining T cells, the scientists obtained blood samples that had been taken from COVID-19 patients in an intensive care unit (ICU). While about half of these patients eventually recovered, the other half died of the disease. By examining samples taken at different times during patients’ stay in the ICU, scientists were able to discern trends they might relate to disease outcome.

Much has already been learned about the immune response of COVID-19 patients during active infection or after recovery. For example, studies in recovering people, including Roan’s previous work, reveal how the immune system can provide long-term immunity. Less clear, however, is how the immune system can protect against serious illness or, conversely, contribute to its aggravation and death. To understand the cause of death, researchers had to compare serious fatal and non-fatal cases.

Using CyTOF, a technique implemented in Roan’s lab that distinguishes between the many types of T cells circulating in the body, scientists have discovered profound differences between the response of T cells in intensive care patients to the virus.

“The T cell response to SARS-CoV-2 increased in patients who were eventually released from the ICU and recovered,” says Roan, who is also an associate professor of urology at UC San Francisco. “But in the patients who eventually died, we sometimes couldn’t detect any T cell response, or their response waned over time.”

The differences also extended to the composition of the T cells of patients who recognize the SARS-CoV-2 virus. In particular, the patients who survived harbored an increasing number of T cells called Th1, which are known to be important fighters of viral infection. Roan’s team discovered molecular features on Th1 cells that could explain why they were able to multiply in these patients.

In contrast, they found that the patients who died had a high number of T cells secreting an inflammatory molecule that would contribute to their worsening lung condition. These patients also had more regulatory T cells that recognized the virus. Regulatory T cells normally help calm the immune response once the infection clears.

“Perhaps in these patients, the regulatory T cells were activated too early and prevented the effector T cells from developing an adequate immune response to SARS-CoV-2,” says Roan. “It could help explain the paltry response of patients to the virus.”

Based on these results, doctors might be able to predict the course of the disease from the relative abundance of regulatory Th1 and T lymphocytes that recognize SARS-CoV-2 in a patient’s blood.

Roan warns, however, “Our results show correlations, not causes. The immune system is complex, with many moving parts and possible interactions between them. Proving the cause of death will require further study.”

Stop the flow of lung cells

Another potential cause of death the team discovered was an increase in the number of T cells capable of infiltrating the lungs of dying patients. In contrast, these cells decreased over time in patients who recovered.

Scientists call these lung cells “spectator T cells” because they are T cells that do not directly recognize the SARS-CoV-2 virus.

“Our study suggests that during severe cases of COVID-19, control T cells are recruited from the blood into the lungs, where they may contribute to immune-mediated disease,” Roan explains.

What triggers the surge in control T cells in severe cases of COVID-19 remains unclear, but may be partly mediated by proteins secreted by the lung that recruit these cells. Either way, stemming their flow to the lungs can help reduce lung damage and speed recovery in patients with severe disease.

This approach is particularly promising, as drugs that oppose a molecule found on the surface of neighboring T cells are already approved for the treatment of metastatic cancer.

“Our next step is to test these drugs in a severe COVID-19 mouse model,” says Roan. “We hope that upon further examination these drugs can quickly be tested as an adjunct treatment for COVID-19.”

Reference: Neidleman J, Luo X, George AF et al. The distinctive features of SARS-CoV-2 specific T cells predict recovery from severe COVID-19. Cell representative. 2021: 109414. do I: 10.1016 / j.celrep.2021.109414

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