A mysterious network of white blood cells that can search out and destroy cells infected with the coronavirus has taken on new importance as epidemiologists continue their search for a vaccine amid doubts that antibodies alone can provide lasting immunity.
These blood cells, called T cells, are like snipers in a platoon of immune system soldiers as they stalk and kill infection. It is a skill set, on a microscopic scale, that scientists hope to use against SARS-CoV-2, the specific coronavirus that causes COVID-19.
The human body, in fact, wages a constant war against invaders, and the production of a vaccine against the coronavirus will require molecular biologists to harness those armaments. That includes B cells, which secrete antibodies that neutralize pathogens, and T cells, which destroy the pathogens and any toxic molecules they produce.
T cells have been thrust into the limelight because recent studies indicate the human body may not retain antibodies produced by B cells for very long, raising questions about whether permanent immunity to COVID-19 is possible after people recover.
Nadia Roan, an associate professor at UCSF and a T cell expert, said the key to a vaccine may be to figure out how to inspire T cells to target the coronavirus even in the absence of antibodies, the workhorses of the human immune system.
Roan and her colleagues found that a robust population of T cells that attack the coronavirus emerge after mild infections, and these cells persist for months and can multiply. The results, which were accepted for publication Aug. 14 in the peer-reviewed journal Cell Reports Medicine, suggest that T cells may play an important role in the battle against the virus.
“We found a diverse collection of T cells recognizing SARS-CoV-2, each serving their own specialized functions,” Roan said. “Importantly, these T cells persisted for over two months after recovery from infection, and were capable of markedly expanding in number.”
The UCSF findings were similar to what researchers at France’s Strasbourg University Hospital found in a preliminary study published recently in medRxiv, an online service that distributes unpublished manuscripts. Both studies found that the T cell response was detectable for at least 69 days in patients recovering from mild cases of COVID-19.
A Swedish study published last week in the scientific journal Cell found SARS-CoV-2-specific T cells in patients, including asymptomatic individuals, who had no detectable antibodies.
The Roan research team plans to monitor T cell responses in patients for six months to see if they are still present.
“It’s kind of encouraging,” said Roan, who works in the UCSF urology department and is an investigator for the Gladstone Institutes, an independent biomedical research organization.
The studies are an example of the complexities scientists face in their accelerated search for a coronavirus vaccine.
Of the 150 potential coronavirus vaccines in various stages of development, at least five elicit both antibody and T cell responses. Those include RNA vaccines developed by the Massachusetts biotechnology company Moderna and New York City firm Pfizer.
The ability to stimulate T cell production, or replication, is expected to be a crucial part of whatever vaccine is developed. Roan and her colleagues recently published a separate study showing that a protein called Interleukin-7 boosted the number of T cells. The Interleukin-7 treatment is also undergoing a clinical trial in the United Kingdom.
“It’s good news for us that these cells that can fight SARS-CoV-2 can expand in numbers,” she said.
Researchers must also figure out how to stimulate T cell growth without causing the immune system to overreact. T cells can, when stimulated too much, attack healthy cells. Physicians say overreactive immune responses, called cytokine storms, have been responsible for many of the most severe cases of COVID-19 and quite a few deaths.
Harnessing T cells isn’t easy, given that researchers don’t completely understand all the ways the virus interacts with the human body. The job requires a deep dive into the diverse collection of cells, amino acids and proteins that make up the human immune system.
There are two types of T cells — known as CD4 and CD8. CD4 cells are known as helpers because they assist all other cells, including the production of antibodies by B cells. The CD8 cells are the body’s assassins, lying in wait in the bone marrow and lymphoid tissues, where they jump out and attack infected cells, according to microbiologists.
It is possible to differentiate between the two using technology called mass cytometry, Roan said. In the past, scientists bunched blood cells together and analyzed them all mixed up like a fruit smoothie. Mass cytometry allows each individual T cell to be identified, measured and marked with a kind of ion bar code.
Roan and her colleagues used the technology to track the slow increase of CD4 and CD8 T cells in one male COVID-19 patient with lymphopenia, extremely low white blood cell counts common in severely ill coronavirus patients. She noted a large increase in CD4 helper cells after 26 days and only a hint of CD8 attackers. Then, 14 days after that, both types of T cells were found in abundance.
The full T cell response, albeit delayed, was so effective that the man was released from the hospital.
“It does suggest that T cells may play a more beneficial role in helping with recovery,” Roan said.
But T cells are only part of the complex picture. The attacking virus binds onto the ACE2 receptors of healthy cells, breaks in and replicates. The body’s immune response flags infected cells by placing fragments of protein, or peptides, on their surface, according to the experts. These peptides inspire T cells to break into action, which in turn can help B cells to make antibodies. Then, antibodies can latch onto the virus and prevent them from binding and entering other healthy cells.
Antibodies are also designed by B cells to match an invading virus in a very specific manner, allowing them to bind tightly and neutralize viral functions. Typically, the stronger the binding, the more effective the antibody is in preventing the pathogen from entering the cell, according to infectious disease specialists.
Viruses, however, are capable of mutating in ways that can take away that perfect match, reducing antibody effectiveness. The influenza virus mutates often, which is why people need a different flu shot every year.
And antibody levels can wane over time, leaving too few of them to block all of the virus particles. That may be another reason people need booster shots with some infectious diseases.
When human antibodies lose their effectiveness in these ways, it can also hamper the ability of scientists to produce effective vaccines. That’s because vaccines are designed to produce viral proteins, called antigens, that in turn elicit people’s immune systems to respond, including through production of antibodies.
Vaccines also can elicit the help of T cells, which recognize infected cells that the antibodies failed to protect.
“T cells can give protection completely absent of antibodies. They help make a stronger response,” said Jason Cyster, a professor in the department of microbiology and immunology at UCSF. “T cells specific for the virus proliferate once they are exposed to the virus and then become aggressive and attack the infected cell.”
A goal of many vaccine developers is to figure out how to harness those unique capabilities. The key to that may be found in the ability of human T cells to develop a kind of memory.
After most T cells are done fighting an infection, a small population of “memory” T cells remains behind, according to Roan. The numbers of these cells, and how long they last, can vary, but these cells have the powerful ability to re-emerge when the same virus strikes again.
“If in the future the person is infected with the same virus, these memory T cells can respond faster and more effectively than the first time around,” Roan said. “That’s in part how vaccines work, by eliciting memory cells.”
The phenomenon can also happen with B cells.
Dr. Jay Levy, a specialist in immunology and virology and a professor of medicine at UCSF, said cell memory is why the vaccine for smallpox has continued to work for decades even though the antibody response goes down 75% six months after people are inoculated.
A recent paper showed that patients who contracted SARS, a coronavirus identified in 2003 in China, had long-lasting T cell immunity at least 17 years after they were infected, Levy said.
Immunity does wane with some diseases, he said, which is why booster shots are sometimes needed for, among others, polio. Repeated exposure to some childhood infections, such as chicken pox and mumps, naturally boosts immunity, he said.
“The original B cell that produces the antibodies stays around, probably in the bone marrow, but probably other places, like the lymph nodes, as memory B cells,” Levy said. “If the antibody starts waning, it doesn’t mean the person can’t respond if the agent comes in again.”
Scientists are focusing on maximizing the effectiveness of these memory cells as they attempt to develop vaccines. But Roan said SARS-CoV-2 is unusual and, for some individuals, the memory response doesn’t occur as predicted.
“We would like to elicit a comprehensive immune response,” Roan said. But “if the antibody response wanes, perhaps the T cells can play an important role.”