For years, scientists regarded natural killer cells as the blunt instrument of the immune system, born to kill. They were thought to travel straight from the bone marrow, where they are manufactured, to the sites of early tumors or infectious agents

Now scientists led by newly promoted head-of-laboratory Christian Münz have learned otherwise. Natural killers, they say, have to be raised. In fact, after emerging from the bone marrow, they accumulate in the tonsils, lymph nodes and spleen. There, the natural killer cells await activation before reacting in one of two distinct modes. In one mode, they secrete cytokines, chemical messenger proteins, which modulate emerging responses from other immune system cells. In the other, they are the well-trained killers of tumors and virus-infected cells. While natural killer cells do provide a crucial first defense against many infectious agents and tumor cells, they do so with more discrimination than raw determination

“Natural killer cells burst forth from the secondary lymphoid tissues, the tonsils, lymph nodes and spleen, and destroy infected and cancerous cells while the T and B cells are still mobilizing,” says Münz. “Without them, threatening conditions can get a strong foothold before any adaptive response kicks in.”

This new insight, published in two separate papers in the February issue of The Journal of Immunology, may lead to new ways for scientists to harness natural killers for therapeutic purposes. Leading oncologists treating human leukemias already track natural killer cell activities after bone marrow transplants. James Young of Rockefeller’s neighboring Memorial Sloan-Kettering Allogenic Bone Marrow and Stem Cell Transplant Service, is one of them. “The emerging data on natural killer cells are helping to move their potential role in transplantation and cancer from conjecture to sound hypotheses,” he says

Münz’s newly established Laboratory of Viral Immunobiology not only explains why the natural killer burst is important — it likely results from mobilization of the cells from lymphoid tissues, and these activated immune cells are discriminating enough to recognize virus-infected and tumor cells — it also affirms a potential strategic change in bone marrow donor matching

In the past, bone marrow donors were selected based on their blood profiles: the closer the match to the patient, the better. But that’s less important when doctors can harvest, multiply and reinject the patient’s own natural killer cells to fight both residual cancer and immune system cells of the patient. Certain mismatches between donor and recipient can actually encourage the donor’s natural killer cells to deliver an extra punch to the cancer and to graft-versus-host disease, the updated logic goes

Münz and his colleagues did not develop this strategy, but part of their aim in understanding where and how natural killers hang out was to determine more effective ways to combat emerging diseases in the body. The Rockefeller scientists are in close contact with clinicians interested in tailoring immune cells including natural killer and dendritic cells, to treat human leukemias

The research may also help Münz and colleagues battle a menace known as the Epstein-Barr virus, a member of the herpes family of viruses. Though most infections are latent, active Epstein-Barr is the source of infectious mononucleosis in many teenagers

Epstein-Barr was also identified as the first human cancer-causing virus. Epstein-Barr transforms the immune system’s B cells and is associated with B cell tumors such as Hodgkin’s disease and Burkitt’s lymphoma. Münz and his colleagues know that the natural killer response is important in establishing immune control against Epstein-Barr

“We have seen that Epstein-Barr transformation of B cells can be delayed by a strong natural killer burst,” says Münz. “Now we are studying how this herpes virus may be targeted by natural killer response.” By learning both what molecular signals activate natural killers in their dialogue with dendritic cells and how viruses can be targeted by natural killers, Münz and his colleagues may be able to artificially stimulate natural killers to heighten their effect and ward off emerging Epstein-Barr associated malignancies

“We’re trying to get a sum of all signals that activate natural killer cells against viruses and tumors and do not cause harm to human tissues,” says Münz. “In the past five years, we’ve learned enough about these cells to extend hopes of their eventual usefulness in medical treatments.”

Before this, natural killer cells were simply the immune system’s natural born killer

January 30, 2004