ABOVE: A human natural killer cell

Scientists have long believed that humans and many other mammals have two types of immune systems: innate and adaptive. The former is driven by natural killer (NK) cells, which attack any cell it identifies as non-self, the latter by B and T cells that form long-term memories of particular antigens they meet so they are more prepared to fight that antigen in the future.

The NK cells are thought to form the first barrier of defense against any incoming pathogen, poking holes in the cells to kill them. Several years ago, researchers discovered that these NK cells may be able to form “memories” of previous antigen exposures and play a role in adaptive immunity, independent of B and T cells—in mice, at least.

Today (May 10), researchers report in Science Immunology the first observation of this NK function in humans, too....

“We were hopeful that if we can show that human natural killer cells also have this vaccine-induced or infection-induced specific memory of prior disease encounter that we could target them with vaccination, and perhaps improve vaccine development, for the protection of people from disease,” Silke Paust, an immunologist at the Scripps Research Institute and the senior author of the study, tells The Scientist

“The previous studies that demonstrated there was pathogen-specific NK cell memory in animal models was a great surprise to the field. This [study] opens up the possibility that vaccination strategies could be developed to induce memory NK cells, along with memory T and B cells. If the findings of the current study . . . can be confirmed, this opens the door to additional means of vaccination,” Mary Markiewicz, an immunologist at Kansas University Medical Center who was not involved in the study, tells The Scientist in an email. 

The study was conducted in two parts. First, the scientists decided on a mouse model that hosts a “humanized” immune system in which the animal’s immune cells are replaced with human ones. Then they exposed some of these mice to an HIV envelope vaccine and left others “naïve” as controls. Next, they harvested NK cells from the livers and spleens of the mice, cultured them separately, and exposed these cells to either another HIV envelope, an influenza virus, an inert protein, or nothing at all.

“If killing is antigen-specific, then the HIV-envelope–primed NK cells will only kill HIV-envelope–loaded targets, but none of the control targets,” says Paust. “This is what we saw.” NK cells from the mice exposed to the HIV antigen reacted when they encountered an HIV protein, but did not respond to the inactive protein, and showed a limited response to the influenza. NK cells from mice that hadn’t been exposed to the HIV envelope protein ignored or had a limited response to every exposure Paust’s team gave them. 

NK cells in a blister on people’s skin caused by chicken pox glycoproteins were active and fighting the antigens, implying that the adaptive memory of these cells had lasted decades.

These results support what her group had found previously, that NK cells can recall past encounters with pathogens. 

But there was one surprise. Only the NK cells harvested from the animals’ livers seemed to “remember” the HIV envelope, not the ones from their spleens. Both groups of NK cells that came from the spleens—those that had been exposed to the vaccination and those that hadn’t—reacted as if they’d never been exposed to the HIV envelope virus.

The second part of the study used actual humans, rather than humanized mice. Paust and her team recruited adults aged 40–60 who had had chicken pox when they were children and injected them with glycoproteins from the chicken pox virus. “It’s similar to a TB test,” she explains, in that people who have had chicken pox will develop a blister-like response on the skin at the site of injection. 

Once the blister formed, scientists collected some of the fluid and isolated NK cells that had been recruited to the site. Unlike NK cells found elsewhere in the body, these cells were active and fighting the antigens, implying that the adaptive memory of these cells had lasted decades.

Paust says she believes the cells were likely to have originated in the liver, based on comparisons to liver-derived cells. “This is as close as we could get in humans,” she says, admitting that this is not a perfect test, but that she hopes clinicians who have access to liver and spleen tissue after surgeries might have the opportunity (with their patient’s consent) to explore further. 

Understanding how NK cells form adaptive memories may help researchers develop more-effective vaccines that stimulate immunity from all three types of capable immune cells. Plus, if scientists can identify biomarkers showing when NK cells are responding to familiar infections, it may provide clues as to why some vaccines are more effective than others. 

Graham Lord, a biologist at King’s College London calls the study “quite exciting” but emphasizes that researchers will still need to explore the biological mechanisms behind the long-term memory in humans before it can translate to useful therapies. 

R. Nikzad et al., “Human natural killer cells mediate adaptive immunity to viral antigens,” Science Immunology, 4:eeat8116, 2019.

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nk natural killer cell immunology immune cell adaptive innate immunity

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