Identification of master regulator for specialised immune cell raises hope in cancer fight.
It is known that natural killer cells, a type of white blood cell prevalent in the body, deliver lethal toxic granules into cells that have become cancerous or infected, causing them to explode. The immune cells hunt and destroy foreign cells in the body, including cancer cells that spread and form tumours. Therefore, it is highly desirable to identify the mechanism which drives these specialised immune cells, as it would offer researchers a new way to develop potential drug targets and cancer treatments. Now, a study from researchers at The Walter and Eliza Hall Institute of Medical Research shows for the first time how the ‘switch’ that turns on these natural killer cells works; the switch, a protein called ID2, works by allowing natural killer cells to become responsive to growth factors in the blood. The team state that their findings will allow the global medical community to think of new strategies to regulate the activity of natural killer cells by targeting the switch and could lead to new treatments. The opensource study is published in the journal Immunity.
Previous studies show that the inhibitor of DNA binding 2 (ID2) is essential for natural killer cell development with its canonical role being to antagonize E-protein function and alternate lineage fate. A growth factor called interleukin-15 (IL-15) keeps natural killer cells active and alive and if it is taken away these cells die. IL-15 signaling is achieved via phosphorylation of its receptor by JAK1 or JAK3. However, it has long been hypothesized that a switch, or master regulator, was controlling this cascade, being essential for the natural killer cell development. Given the absence of natural killer cells in both ID2 and IL-15 mice, the current study investigated natural killer cell dependency on these two factors acting on a common pathway.
The current study shows a key role for ID2 in regulating IL-15 receptor signaling and homeostasis of natural killer cells by repressing multiple E-protein target genes. Results show that ID2 deletion in mature natural killer cells was incompatible with their homeostasis due to impaired IL-15 receptor signaling and metabolic function. Data findings show that this could be rescued by strong IL-15 receptor stimulation or genetic ablation of the gene Socs3.
The group state that during NK cell maturation, an inverse correlation between E-protein target genes and ID2 was observed. They go on to add that these results shift the current paradigm on the role of ID2, indicating that it is required not only to antagonize E-proteins during natural killer cell commitment, it is also constantly required to titrate E-protein activity to regulate natural killer cell fitness and responsiveness to IL-15. The lab note that they can now make natural killer cells appear even when this switch is missing, purely by supplying more growth factor to the specific environment; also the natural killer cell switch could potentially be turned off in instances in which these cells proved damaging.
The team surmise that they have identified how natural killer cells are born and how they’re maintained in the human body. They go on to add that their findings mark the first time a study has overcome immune deficiencies in cells that are missing the switch by ‘tricking’ the cells into becoming natural killer cells using growth factor. For the future, the researchers state that the switch that controls these immune cells could also be manipulated to fight viral infections or to help patients whose immune systems have not developed properly because their bodies lack natural killer cells. They go on to conclude that if they can give an advantage to natural killer cells by boosting their activity or numbers or survival in the body then the global medical community can try to win that fight against cancer.