In recent months, a number of scientific studies have found that some people have immune systems with cells that are tailored to fight the coronavirus despite having never been exposed to it.
The likely explanation is found in a special cell in the human immune system known as a T cell. T cells are a type of white blood cell that help regulate the immune system’s response to a pathogen such as the coronavirus. One type of T cell is CD8+, and it attacks and kills cells in the body that are infected with a pathogen. Another type is CD4+, and it is a “helper” cell that assists other cells in the immune system.
After the body fights off a pathogen, the immune system retains some of the T cells as “memory cells.” If the pathogen returns, the memory cells can give the body a jump in fighting it.
It is possible that some people have T cells that are primed to fight the coronavirus even though they have never been infected with it. These are “cross-reactive” T cells, ones that can fight more than one pathogen.
At least six studies have found cross-reactive T cells that target the coronavirus in individuals with no known exposure to the virus. A study in the journal Cell examined blood samples taken in the United States from 2015 to 2018, well before the coronavirus appeared. About 50% of the samples had cross-reactive T cells that targeted the coronavirus. Studies in Germany, Singapore, Sweden, and the United Kingdom likewise found cross-reactive T cells in people who had not been exposed to the coronavirus. Another study in Nature found cross-reactive T cells in people that had been exposed to SARS virus back in 2003, suggesting that the SARS virus may have primed the T cells.
This is far from unprecedented. “I think a lack of any preexisting immunological response may be more the exception than the rule,” said Peter Doshi, a professor of pharmaceutical health services research at the University of Maryland. In 2009, for example, researchers at the Centers for Disease Control and Prevention found that at least a third of people over age 60 had preexisting T cells that reacted to the H1N1 swine flu.
Although the Nature study connected the cross-reactive T cells to SARS, most studies hypothesized that they were related to common cold viruses similar to the coronavirus.
“Our hypothesis, of course, was that it’s so-called common cold coronaviruses because they’re closely related,” Daniela Weiskopf, a professor at the La Jolla Institute for Immunology, told the British Medical Journal. “We have really shown that this is a true immune memory, and it is derived, in part, from common cold viruses.” In a paper in Science, Weiskopf and her colleagues found cross-reactive T cells that reacted to both the coronavirus and to four different common cold viruses.
Yet common cold viruses may not be the main source of cross-reactive T cells. A new study by researchers at the UCL Genetics Institute at University College London examined the substance that triggers T cells into creating an immune response, known as an epitope. Epitopes are chains of amino acids that show up on cells infected by a virus. The study, which has not yet been peer-reviewed, examined epitopes that trigger the T cells that react to the coronavirus, and over half of the epitopes were not related to common cold viruses.
“The cross-reactive T cells observed by multiple labs across the world do not seem to have been primed from any single coronavirus,” said Cedric Tan, a student at University College London and one of the authors of the study. Tan added that the study could not completely rule out that some combination of common cold viruses might account for the cross-reactive T cells.
But he suggested two other explanations. First, a combination of other viruses or nonviral organisms such as bacteria may have primed the cross-reactive T cells. However, he noted that thus far, they had found no such organism that was likely to have primed the T cells.
The other explanation is that people already have cross-reactive T cells in their immune systems.
“T cells [might be] inherently and perhaps randomly cross-reactive, and we happen to have some T cells that can recognize [the coronavirus],” Tan said. But he added that explanation was “the most speculative.”
Cross-reactive T cells also have implications for herd immunity. Herd immunity occurs when a large portion of the population, the “herd,” becomes immune to a virus through a combination of people getting infected with the virus and people getting vaccinated. Once herd immunity has been achieved, it is harder for the virus to spread to the smaller part of the population that has not been infected or vaccinated. Fewer people would need to be infected or vaccinated if a significant portion of the population had a preexisting immunity.
Doshi, writing in the British Medical Journal in September, suggested that preexisting immunity might explain the patterns of infection in some cities. “The immunologists I spoke to agreed that T cells could be a key factor that explains why places like New York, London, and Stockholm seem to have experienced a wave of infections and no subsequent resurgence,” Doshi wrote. “This would be because protective levels of immunity … the result of a combination of pre-existing and newly formed immune responses, could now exist in the population, preventing an epidemic rise in new infections.”
Yet all of those cities have seen a resurgence in coronavirus infections in recent months. When asked if the resurgence in those places undermined the theory of preexisting immunity, Doshi replied, “No simple answer suffices. Take New York, for example. The resurgence you’re referring to is a resurgence of positive PCR test results; there hasn’t been a similar resurgence of deaths in New York.”
Tan replied that theories about a preexisting immunity protecting against resurgence are “likely to be purely speculative. There has been no convincing evidence so far for any protective effect of T cell cross-reactivity. We don’t exactly know if these cross-reactive T cells can prevent infection or how they affect disease severity.”
Indeed, some recent evidence suggests that cross-reactive T cells may not provide much protection against coronavirus infection. A study recently published in Immunity found that cross-reactive T cells were not particularly effective at targeting infected cells. The authors concluded that their findings “argue against a protective role for [cold virus]-reactive T cells in SARS-CoV-2 infection.”
