Natural-born killers identified by British researchers

LONDON—A team of British researchers, led by Dr. Hugh Bradyof Imperial College London's Department of Life Sciences and publishing in thejournal Nature Immunology inmid-September, have identified the master gene that causes blood stem cells toturn into disease-fighting natural killer (NK) immune cells. This is adiscovery that the team, which included researchers from University CollegeLondon and the Medical Research Council's National Institute for MedicalResearch, believes could one day help scientists boost the body's production ofthese frontline tumor-killing cells, creating new ways to treat cancer.

NK cells represent a distinct lymphocyte subset that play a"central role in innate immunity," the researchers note, adding that NK cellsseem more and more clearly to serve important functions in influencing thenature of the adaptive immune response, such as tumor immunosurveillance andelimination of microbial infection.

"A great deal of progress has been made in delineating thecytotoxic mechanisms of NK cell action, specifically events that control targetcell recognition and receptor signaling, as well as the production ofproinflammatory cytokines such as interferon-gamma (IFN-gamma)," the team wrotein their article, "The basic leucine zipper transcription factor NFIL3 isessential for natural killer cell development."

"However, the molecular basis of NK cell development is muchless well understood and has been characterized as one of the most importantproblems to be addressed in NK cell biology," they continued. "Greaterknowledge of how NK cells develop into functional effector cells is essentialfor understanding their contribution to disease processes as well as forexploiting their therapeutic potential."

The researchers were initially studying the effect of E4bp4in a very rare but fatal form of childhood leukemia when they discovered itsimportance for NK cells.

Currently, NK cells that have been isolated from donatedblood will be used at times to treat cancer. However, but the effectiveness ofsuch donated cells is limited because NK cells can be slightly differentbetween one person to another. With this new research in their collectivepockets, the British researchers hope to move on to finding a pharmaceuticaltreatment for cancer patients that will react with the protein expressed bytheir E4bp4 gene they identified. This would, theoretically, cause their bodiesto produce a higher number of NK cells than normal, to increase the chances ofsuccessfully destroying tumor, Brady indicates.

"If increased numbers of the patient's own blood stem cellscould be coerced into differentiating into NK cells, via drug treatment, wewould be able to bolster the body's cancer-fighting force, without having todeal with the problems of donor incompatibility," he says.

In looking at potential immunotherapy applications, the teamwrote that that researchers and pharma developers could benefit both from theability to expand specific subpopulations of NK cells ex vivo or to enhance NK cell numbers in vivo—both of which would be "extremely powerful tools."

Over the course of their work, the team knocked out the E4bp4gene in a mouse model, creating what they say was the world's first animalmodel entirely lacking NK cells yet possessing all other blood cells and immunecells. They believe this breakthrough model will not only benefit cancertherapy but also help solve some mysteries around the role of NK cells inautoimmune diseases, such as diabetes and multiple sclerosis.

Some scientists think that these diseases are caused bymalfunctioning NK cells that turn on the body and attack healthy cells, causingdisease instead of fighting it. Brady notes. Clarifying NK cells' role couldlead to new ways of treating these conditions.

This new mouse model should also allow medical researchers,for the first time, to discover if NK cell malfunction is behind even more medicalconditions than those already notes, such as inflammatory conditions,persistent viral infections, female infertility and graft rejection.

"Since shortly after they were discovered in the 1970s, somescientists have suspected that the vital disease-fighting NK cells couldthemselves be behind a number of serious medical conditions, when theymalfunction," Brady notes. "Now finally, with our discovery of the NK cellmaster gene and subsequent creation of our mouse model, we will be able to findout if the progression of these diseases is impeded or aided by the removal ofNK cells from the equation. This will solve the often-debated question ofwhether NK cells are always the 'good guys' or if, in certain circumstances,they cause more harm than good."

The study was funded by the non-profit organizationsCHILDREN with LEUKAEMIA and Leukaemia Research.