amfAR, The Foundation for AIDS Research

Natural Killers Adapt

By Marcella Flores M.P.H., Ph.D.

reevesDr. R. Keith Reeves HIV vaccine strategists have a new and unexpected target in their sights: the natural killer (NK) cell. Writing in the September issue of Nature Immunology, researchers led by amfAR grantees Drs. R. Keith Reeves and Dan Barouch at Beth Israel Deaconess Medical Center in Boston reported, for the first time in primates, a new role for NK cells in the adaptive immune response.

The adaptive immune response, one of the two main arms of the immune system, provides long-lasting protection by creating memory of specific invading pathogens. This memory can be quickly recalled during subsequent encounters and is the basis on which vaccines are designed. The second arm of the immune system, innate immunity, delivers an immediate and potent, if unspecific, counterattack against infectious agents. NK cells have been traditionally thought to belong to the latter group, broadly killing target cells that are either virus-infected or cancerous.

The idea that NK cells belong strictly to the innate immune response began to change when studies in mice suggested that they can have a long-lasting memory of previously encountered pathogens. Reeves and Barouch, with colleagues from the New England Primate Research Center, Harvard Medical School, Ragon Institute of Massachusetts General Hospital, and the Heinrich-Pette-Institut in Germany, used macaques as models of HIV in humans to demonstrate that these special "adaptive NK cells" also exist in primates, and are major players in the immune response to HIV vaccines.

The researchers first showed that the NK cells were identifying their target cells based on whether they "matched" the virus in their memory bank. Then, to verify that the NK cells met the second criterion of adaptive immunity (i.e., a long-lasting response), they vaccinated animals with one of two different HIV-specific vaccines and waited five years before testing them. Again, they found that the NK cells, which first saw the vaccine five years ago, recognized and killed the matching target cells, leaving the mismatched cells largely untouched.

These results show that NK cells could be important in human vaccine strategies and we should move beyond targeting traditional cellular members of the adaptive immune response. "This gives us a brand new target," said Reeves. "We've been basing 30 years of vaccine research on essentially two types of adaptive immunity and now we have a brand new target…it is a really exciting proposition and it's a wide open area." Assessing NK cells' role in vaccine potency, as well as harnessing their various killing mechanisms, could be crucial in devising the most effective HIV vaccine.

Dr. Flores is amfAR's associate director of research.