While whole blood transcriptomics is helpful, it can only provide a snapshot of what is going on. Next, the scientists turned to a technique called CITE-seq. This allowed them to find out which cells expressed which genes differently between males and females, and which specific proteins they were producing. The best part is that CITE-seq can be used on the same blood samples taken from patients. “There’s only one type of sample, and you just measure it,” Tsang said.
A particular type of cell appears to contribute to the response to the flu vaccine: potent memory T cells (produced after infection to “remember” specific pathogens they encountered) that express a receptor called GPR56 on their surface. It turned out that men who had recovered from Covid had more of these cells than women who had recovered from Covid and healthy controls. But why would these seemingly coronavirus-related cells respond to a flu shot?
“The typical assumption is that infection creates cells that are unique to viruses,” Tsang said. But as he explained, that doesn’t have to be the case. Other more broadly reactive immune cells can also be activated. These cells, known as “bystander cells,” responded very quickly to the vaccination, sounding the alarm and causing the immune system to produce antibodies in response.
In fact, when the scientists examined the GPR56-positive T cells, they found similarities to bystander cells known to be activated during acute Covid infection. They therefore hypothesize that these GPR56-positive cells may function in a manner similar to bystander cells, persisting in the body after Covid and initiating an immune response to other invaders, in this case the flu vaccine.
To prove the theory, scientists need to understand how GPR56-positive T cells respond to something like infection or vaccination. When they isolated these T cells, grew them in a dish, and stimulated them with small signaling molecules called cytokines known to be produced during infection or vaccination, the scientists found that the T cells secreted high levels of inflammation proteins, which have been found in Covid-recovered men – providing evidence that this cell type can indeed trigger an immune response that ultimately produces more antibodies to the flu. They found conclusive evidence.
Consiglio is curious to see what effect these immune system differences between men and women who have recovered from Covid will have in the future when a person is actually infected with the flu or another virus. Observational and previous infections also raise questions about how other factors influence the immune response. Sabra Klein, a microbiologist at Johns Hopkins University, is interested in understanding how factors such as age affect the equation, and possibly create a sliding scale for immune responses. “We often treat these types of variables as binary variables — are you young or old, are you male or female — and we often don’t do enough to look at these intersections,” Klein said.
Ultimately, Tsang and his team hope the results can help scientists design more effective vaccines, or find ways to predict how a person will respond to an infection. They wondered whether these GPR-positive cells could be more effective at eliciting responses to pathogens. On the other hand, scientists are also curious about how these cells (and others) function during autoimmunity, when the immune system is overactive.
Until then, they will continue to understand the complexity of the immune system — especially how it has evolved during the pandemic. “We’ve always thought of the human immune system as a very diverse natural experiment,” Tsang said. Thanks to the pandemic, the opportunity to learn from this experiment is much greater—meaning we now know more about why our immune systems are so different, and how they change over time.
