by Nick Miller

Stephen Waggoner, PhD.

In a study of mice, Dr. Stephen Waggoner and colleagues found that NK cells suppressed the development of T and B cells equipped with the programmed memory needed to attack future viral infections. Findings were published in Nature Communications.

Stephen Waggoner, PhD, wants to harness the innate abilities of natural born killers to improve medicine and save lives. The immunologist and researcher – a member of the Center for Autoimmune Genomics and Etiology at Cincinnati Children’s – leads a team of scientists who study the immune system’s natural killer cells (NK cells). They are using a $2.5-million Avant-Garde grant from the National Institutes of Health to help develop vaccines against viruses that have long lacked effective inoculations, including HIV, tuberculosis and hepatitis C.

Their work so far reveals that the aggressive nature of NK cells can prevent other elements of the immune system from producing the response that vaccines are designed to invoke. Now, the team is searching for safe ways to tame that aggression.

“The primary role of NK cells is to eliminate unwanted infectious or cancerous cells,” Waggoner says. “While T and B cells in the immune system serve in a similar capacity, through recognition of specific attributes of these unwanted cells, they require a lengthy process of arming similar to the assembly and loading of a firearm. In contrast, NK cells are first responders and more like a loaded gun with the safety off, capable of rapidly killing a broad array of infected or cancerous cells.”

This gunslinger mentality can be beneficial when the target is a cancer cell or herpes virus. However, Waggoner and other researchers have found NK cells can keep vaccines from working properly by subduing other immune cells that must be stimulated to battle life-threatening infections. Thus, NK cells can become too much of a good thing.

DOUBLE IDENTITY

NK cells have dual roles in immunity, Waggoner says. As first-response soldiers, they attack whatever foreign invaders they encounter. As sentinels, NK cells also play a role in deciding when to summon reinforcements from other parts of the immune system, including our T cells and B cells, and how many.

Scientists are still working to understand exactly when, why and how NK cells affect the immune system’s on-or-off process. Waggoner and colleagues shed new light on how NK cells work in a paper published earlier this year in Nature Communications.

The study analyzed mice infected with lymphocytic choriomeningitis virus (LCMV), a rodent virus that can cause diseases of the central nervous system, liver, and lungs. The researchers found that NK cells suppress the development of T and B cells that should be programmed with a sustained memory for staging a prolonged attack against LCMV.

By subduing T and B cells at a crucial point, NK cells allowed the infection to take root and spread. This is important in the context of vaccines because part of a vaccine’s function includes imparting programmed memory for immune cells against a specific virus, Waggoner explains. If NK cells subdue the development of these programmed memory cells, the vaccine is not effective.

The aggressive nature of NK cells can prevent the immune system response that vaccines are designed to invoke.

The aggressive nature of NK cells can prevent the immune system response that vaccines are designed to invoke.

TIMING MAY BE EVERYTHING

Finding a way to inhibit NK cells could increase vaccine effectiveness against viruses that cause malaria, AIDS, tuberculosis and some forms of cancer. But this approach is not risk-free.

In studies of mice, Waggoner’s team has shown that inhibiting or deleting NK cells does stimulate a bigger and better immune response. However, long-term absence of NK cells also can ramp up other immune components to the point where mice develop markers of autoimmune disease in their kidneys.

“The practical question is how to take the brake off?” asks Waggoner. “It’s unrealistic to think we can go into people like a mouse and deplete those cells, because they might be preventing a herpes infection or cancer. We want to maximize the B and T cell response in a targeted way that doesn’t entirely remove the NK cell side of the coin.”

The team’s research now focuses on learning more specifics about how NK cells function in their respective beneficial and harmful roles, and then targeting the cells precisely to boost the effectiveness of vaccines. The researchers are teasing out different genes, proteins and biological mechanisms that might make this possible. Studies like the one in Nature Communications suggest this could lead to a drug or formulation that serves as an adjuvant therapy to a vaccine or that could part of the vaccine itself.

“What if you could include a small molecule in a vaccine that binds to NK cells for a few days to keep them from activating?” Waggoner says. “We want something specific to repress NK cells during a certain period of time, and then allow them to come back to full
functionality.”