MRC National Institute for Medical Research, London
Science for Health
Natural Killer master gene identified
14 September 2009
Natural Killer (NK) cells are lymphocytes but are less well characterised than T and B cells. NK cells can directly kill target cells ranging from microbial-infected cells to cancer cells. NK cells also produce pro-inflammatory cytokines such as Interferon-γ, activate dendritic cells and even prime T and B cells. Altered NK cell function is thought to be central to the pathology of multiple disease states including cancer, autoimmune disorders, inflammatory conditions, persistent viral infections, female infertility and graft rejection. Harnessing the therapeutic potential of NK cells has therefore been a goal of medical research for some time. A major obstacle has been our lack of understanding of the regulation of NK cell production as well as a suitable mouse model in which to study the precise role of NK cells.
In collaboration with Dimitris Kioussis (pictured) and members of his lab in NIMR's Division of Molecular Immunology, Duncan Gascoyne and Hugh Brady have identified the gene E4bp4 as critical to NK cell lineage commitment. After generating mice lacking E4bp4 they found that these mice have no NK cells but that other related cell types such as memory T cells and NKT cells were unaffected. Transducing blood stem cells with E4bp4 is sufficient to induce them to differentiate into NK cells. E4bp4 regulates a genetic pathway, also including Gata3 and Id2, which is specifically responsible for producing NK cells.
Our findings provide a master key that will allow us to unlock the gene network that controls the formation of mature NK cells. This should let us identify molecular targets for drugs to manipulate NK cell numbers and activity. In addition, the mouse model is the only one available to specifically remove all functional NK cells. This will allow us to clear up once and for all the requirement for NK cells to prevent or promote various disease states.
Hugh Brady
Original article
The research findings are published in full in:
Duncan M. Gascoyne, Elaine Long, Henrique Veiga-Fernandes, Jasper de Boer, Owen Williams, Benedict Seddon, Mark Coles, Dimitris Kioussis, and Hugh J.M. Brady (2009)
The bZIP transcription factor E4BP4 is essential for natural killer cell development
Nature Immunology, epub ahead of print. Publisher abstract.
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