Killer cells craftier than thought

In the rough-and-tumble world of your immune system, cells don't come any tougher than the "natural killer" cells the body deploys as front-line troops to battle infection.

"Natural killer cells are kind of the 'Marines' of the immune system, first on the beach to hold off the enemy," says microbiologist Lewis Lanier of the University of California, San Francisco.

And just like the real Marines, a study led by Lanier's co-author, Joseph Sun, shows that natural killer cells turn out to be a lot craftier than their reputation might suggest. Released Sunday by the journal Nature, the study overturns a bit of conventional scientific wisdom about the nature and origins of our immune system.

Immune system cells respond to invaders, from bacteria to viruses to allergens, in two stages. First, "innate" immune cells hassle invaders right away after a wound or infection, natural killer cells in the forefront. Always circulating in the bloodstream, natural killer cells burst virus-infected (or cancerous) cells after hooking on to distinctive proteins on their infected surfaces.

Innate cells are thought to be short-lived, from a few days to weeks, equipped with surfaces that hook onto a broad range of invaders, and serve as general-purpose protectors. From an evolutionary standpoint, the innate system looks like the first and simplest line of defense that animals developed, Lanier says. "Innate cells hold the fort until the 'adaptive' immune cells can beat off the attack."

The defining characteristic of innate immune cells had been that they exhibited no "memory" of past infections, says Harvard's Ulrich von Andrian.

The second stage of the immune system response comes from the "adaptive" immune system, so-called B and T cells, which in contrast take about a week to grow in response to infection, and are specifically tuned to the invader (this is one reason it takes so long to get rid of a cold.) Unlike innate immune cells, some of these adaptive cells live a long time, retaining a "memory" of the invader that makes for a stronger response to the next attack.

"Conventional wisdom was that 'natural killer' cells don't have this memory because they only live two to three weeks," Lanier says. But a 2006 Nature Immunology study from von Andrian's lab suggesting that natural killer cells live at least a month in mice led Lanier's group to take a second look at this certainty.

In the new study, the researchers gave mice, whose mammalian immune system works just like the human one, staggered cytomegalovirus infections and watched how long their natural killer cells responded. Cytomegalovirus is endemic to humanity; at least half of the population has it. "I have it, you get it in pre-school," says Lanier. Natural killer cells are tuned to respond to these type of endemic viruses, particularly the herpes family, which includes chicken pox and the eponymous sexually-transmitted disease. "Once you have them, they stay hidden inside you, so it makes sense for immune cells to preferentially aim to tamp down their activity," Lanier says.

The researchers had wiped out the adaptive immune systems of the mice with radiation, prior to infecting them, to prevent those "memory" cells from complicating their analysis. Monitoring blood counts, the team found a virus-specific natural killer cell family grew and multiplied in numbers 100 times higher than normal in the spleen, and 1,000 times higher-than-normal in the liver, of the mice. "That's more like the adaptive immune system, than the innate," notes Lanier. Some of these virus-specific natural killer cells lived for at least 70 days and when transferred into another just-infected mouse delivered an immune response 10 times more powerful than regular natural killer cells. Just like adaptive immune cells, "NK cells have the ability to 'remember' previously encountered pathogens and are able to mediate more efficient protective immunity against subsequent infection," concludes the study.

"The textbooks are wrong, or at least, need to be amended," says von Andrian, who was not part of the new study. "Even this study could be just the tip of the iceberg, given the many subsets of natural killers cell that exist." Past studies his group has submitted suggesting results along these lines have met resistance from reviewers skeptical that "innate" immune cells could demonstrate memory, von Andrian adds.

The trick to demonstrating the "memory" of natural killer cells was using the right kind of virus, ones the cells were predisposed to destroy, to test their longevity, Lanier says.

A whole new approach to vaccination might result from the natural killer cell finding, suggests Lanier, knowing now that they 'remember' past invaders. "It won't work against influenza, but might against the virus families that the cells are primed to respond to already," Lanier says. The finding might explain some things about the reappearance of shingles, where chicken pox hidden in the nervous system can reappear to strike often-elderly patients as well.

For immunologists, the finding moves natural killer cells from the innate immune system to "kind of an intermediate" place in the evolution of the immune system, Lanier says, with natural killer cells representing a transitory cell type between the innate and adaptive immune system. "Natural killer cells might be a 'missing link,' in that sense," Lanier concludes.