New insights into disease-fighting 'natural killer' (NK) cells should help scientists to produce them more effectively. This could lead to better therapies to combat leukaemia and other diseases.
The work was led by researchers at Imperial College London and the Medical Research Council's National Institute for Medical Research (NIMR) who worked alongside colleagues at King's College London and the University of Toronto in Canada.
NK cells are a type of white blood cell that scan the human body for cells that are cancerous or infected with a virus or a bacterial pathogen, to target and destroy them. NK 'hit men' are one of the body's first lines of defence against cancer.
Scientists have already developed a form of immunotherapy using NK cells, which works by isolating NK cells from donated blood then expanding them in sterile conditions, before injecting them into a patient. This technique has been shown to be effective in treating some forms of leukaemia and it is already in clinical use, but each patient needs up to a billion NK cells and successfully growing this number of cells has proved very difficult.
In the new study, the researchers have made discoveries about how NK cells are produced that could ultimately help scientists to generate a greater number of robust NK cells in culture, to treat leukaemia and other cancers more effectively.
A previous study carried out by the same team revealed that a gene called E4bp4 is an essential gene that has to be switched on to allow the immune system to produce disease-fighting NK cells. The new work shows that E4bp4 is the critical gene that allows blood stem cell progenitor cells to make the decision to turn into NK cells.
The research uncovers a kind of decision tree that genes follow in order to tell the body to produce NK cells. It suggests that E4bp4 is at the top of a genetic hierarchy and that it regulates other genes further downstream, including genes known as Eomes and Id2, which also play an important role in promoting NK cell production.
The researchers reached their conclusions after knocking out E4bp4 in a mouse model. They found that blood stem cells first go through a stage where they become progenitor cells before fully committing to one particular blood cell type such as NK cells or red blood cells or platelets. The progenitor cells (NKPs) that become NK cells have only recently been identified. The new study shows that E4bp4 is essential for the formation of NKPs and that the E4bp4 gene is switched on in blood stem cells. The researchers tested many genes known to have roles in the function and production of NK cells but found that only Eomes and Id2 are essential to allow E4bp4 to direct the production of fully functional mature NK cells.
Dr Andreas Wack of NIMR said: "This work beautifully complements our recent study that showed differences in E4bp4 requirements between conventional NK cells derived from bone marrow and other NK cell populations. Conventional NK cells are E4bp4 dependent and have high levels of Eomes. This is in line with our new results indicating that Eomes is directly controlled by E4bp4. In contrast, the E4BP4 independent NK cell populations identified earlier had low levels of Eomes."
Dr Hugh Brady of Imperial College London added: "We are excited to find that E4bp4 has such a crucial role in determining the decisive point where blood progenitor cells become NK cells. We are now starting to apply this to human blood stem cells to work out how switching on E4bp4 can allow us to make lots of robust human NK cells in culture.
"We are hoping to make human NK cells that will have improved survival and be very toxic to cancer cells when transfused into patients. Hopefully, this will allow a big reduction in the number of NK cells needed to treat an individual patient."
The paper, The transcription factor E4bp4/Nfil3 controls commitment to the NK lineage and directly regulates Eomes and Id2 expression, is published in the Journal of Experimental Medicine.
