The key gene that causes blood stem cells to become the immune system's disease-fighting 'Natural Killer' (NK) cells has been identified for the first time. UK researchers were studying the gene responsible, named E4bp4, to investigate its effects on a rare but fatal form of childhood leukaemia when they stumbled upon its apparent role as a master switch for the production of NK cells. The scientists, from University College London, Imperial College London, and the Medical Research Council's National Institute for Medical Research, published their research in the journal Nature Immunology. The team hopes that its findings will lead to a better understanding of, and eventually the development of new treatments for, a wide range of diseases including cancer, diabetes and multiple sclerosis (MS).
NK cells develop mainly in bone marrow and then, when mature, migrate to other organs such as the spleen and lymph nodes where they protect the body in a non-specific way as part of the innate immune system. They don't learn the makeup of pathogens but provide a broad first line of response, rapidly killing off viruses, bacterial infections and tumour cells. The UK researchers engineered mice that lacked the E4bp4 gene - the concentration of NK cells in their spleen was found to be lower than normal, and further investigation confirmed that there were low levels of both mature and immature NK cells in their bone marrow. Also, stem cells taken from the bone marrow of the mutant mice did not develop into NK cells outside the body - something which can normally be instigated after particular chemicals have been applied. All of these findings point to E4bp4 as being a 'master-switch' controlling the production of NK cells, and this knowledge could have far reaching consequences. 'If increased numbers of the patient's own blood stem cells could be coerced into differentiating into NK cells, we would be able to bolster the body's cancer-fighting force, without having to deal with the problems of donor incompatibility,' said Dr Hugh Brady, lead researcher on the study.
However, rogue NK cells have been implicated in autoimmune diseases such as diabetes and MS where the immune system attacks the body and, more recently, abnormally high levels of NK cells have also been identified as a possible cause of recurrent miscarriages. 'Since shortly after they were discovered in the 1970s some scientists have suspected that the vital disease-fighting NK cells could themselves be behind a number of serious medical conditions, when they malfunction,' said Dr. Brady. 'Now finally, with our discovery of the NK cell master gene and subsequent creation of our mouse model, we will be able to find out if the progression of these diseases is impeded or aided by the removal of NK cells from the equation,' he continued, adding: 'This will solve the often-debated question of whether NK cells are always the good guys, or if in certain circumstances they cause more harm than good.'
Many newspapers have discussed how a 'drug that boots NK cell numbers' would be especially powerful against multiple forms of cancer, but at this stage it is not clear by what mechanism such a drug would work, and the successful development of any such drug is likely to be far in the future. Further research will be needed to first translate these new findings to humans, which will be inevitably followed by many years of testing for safety and efficacy. Nevertheless, Brady and his team hope to use the mouse model in the near future to discover if NK cell malfunction is behind other medical conditions such as female infertility, graft rejection, persistent viral infections and certain inflammatory conditions.