Covid may increase your response to flu vaccines if you are a man
Although whole blood transcriptomics was useful, it provided only a general picture of what was happening. The scientists then turned to a technique called CITE-seq. This allowed them to figure out which cells express which genes differently in men and women, and which specific proteins they make. The best part is that CITE-seq could be used with the same blood samples taken from patients. “There is only one type of sample, and you just measure it,” says Tsang.
A particular type of cell appears to contribute to the response to the flu vaccine: efficient memory T cells (which form after infection and can “remember” the particular pathogen they encounter) with a receptor called GPR56 expressed on their surface. As it turned out, men who recovered from Covid had more of these cells compared to women who recovered from Covid and healthy controls. But why do these seemingly Covid-related cells react to the flu vaccine?
“The canonical assumption is that the infection will generate virus-specific cells,” says Tsang. But, as he explains, this is not necessarily the case. Other more widely reactive immune cells may also be activated. Known as “witness cells,” they respond very quickly to vaccinations by sending out alarm signals that cause the immune system to produce antibodies in response.
Indeed, when the scientists examined GPR56-positive T cells, they found that they bore similarities to the bystander cells already known to be activated during acute Covid infection. So they hypothesized that these GPR56-positive cells probably acted like bystander cells left in the body after Covid and triggering an immune response to other invaders—in this case, the flu vaccine.
To prove this theory, scientists needed to see how GPR56-positive T cells respond to something that looks like an infection or vaccination. When they isolated these T cells, cultured them in a petri dish, and stimulated them with small signaling molecules called cytokines, which are known to be produced during infection or vaccination, the scientists found that the T cells secreted high levels of inflammatory proteins, which were found in men who recovered from Covid, suggesting that this type of cell may indeed have triggered an immune response that eventually led to more flu antibodies. They found their smoking gun.
Consiglio is curious to see in the future what effect these differences in the immune system between men and women recovering from Covid have when a person is actually infected with the flu or another virus. Consideration of gender and previous infections also raises the question of how other factors may influence the immune response. Sabra Klein, a microbiologist at Johns Hopkins University, is interested in seeing how something like age can also factor into the equation and possibly create a sliding scale of immune responses. “We often view these kinds of variables as binary—are you young or old, are you male or female—and often don’t do enough to explore these intersections,” says Klein.
Ultimately, Tsang and his team hope these results will help scientists develop better vaccines or find ways to predict how a person might react to an infection. They want to find out if these GPR-positive cells can be more effectively prepared to respond to a pathogen. 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 appreciate the complexities of the immune system, especially how it evolved during the pandemic. “We’ve always thought about looking at the human immune system as a very diverse natural experiment,” says Tsang. Thanks to the pandemic, the opportunity to learn from this experiment has become much wider, which means we now know more about why our immune systems are so different and how they change over time.