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Credit: Walter and Eliza Hall
Institute of Medical Research
New research suggests the Mcl-1 protein is crucial for the survival of natural killer (NK) cells and, therefore, innate immune responses.
Researchers deleted Mcl-1 from NK cells in mice and observed a loss of the cells from all tissues.
This made the mice more receptive to allogeneic hematopoietic stem cell transplants and resistant to toxic shock following a sepsis challenge, but it also made the mice susceptible to melanoma metastases.
The researchers believe their findings, published in Nature Communications, will help to determine how NK cells can be manipulated to treat a range of disorders.
They said Mcl-1 could be a target for boosting or depleting NK cell populations when necessary.
The researchers first discovered that Mcl-1 is highly expressed in NK cells. And Mcl-1 is regulated by IL-15 in a dose-dependent manner via STAT5 phosphorylation and subsequent binding to the 3′-UTR of Mcl-1.
“We showed Mcl-1 levels inside the cell increase in response to [IL-15],” said study author Nick Huntington, PhD, of the Walter and Eliza Hall Institute of Medical Research in Victoria, Australia.
“We previously knew IL-15 boosted production and survival of natural killer cells, and we have shown that IL-15 does this by initiating a cascade of signals that tell the natural killer cell to produce Mcl-1 to keep it alive.”
To further explore this phenomenon, the researchers deleted Mcl-1 from NK cells in mice and observed depletion of the cells in all tissues. The team said this was the result of a failure to antagonize pro-apoptotic proteins in the outer mitochondrial membrane.
Additional experiments showed that the mice needed the NK cells to fight off invading melanoma cells that had spread past the original cancer site.
“Without natural killer cells, the body was unable to destroy melanoma metastases that had spread throughout the body, and the cancers overwhelmed the lungs,” Dr Huntington said.
However, the loss of NK cells also made mice more receptive to allogeneic stem cell transplants and resistant to toxic shock after polymicrobial sepsis challenge.
“Natural killer cells led the response that caused rejection of donor stem cells in bone marrow transplantations,” Dr Huntington said. “They also produced inflammatory signals that can result in toxic shock syndrome, a potentially fatal illness caused by bacterial toxins that causes a whole-body inflammatory reaction.”
The researchers said these results clearly show a non-redundant pathway linking IL-15 to Mcl-1 in the maintenance of NK cells and innate immune responses.
Dr Huntington said the discovery provides a solid lead to look for ways of boosting or depleting NK cells when necessary.
“Now that we know the critical importance of Mcl-1 in the survival of natural killer cells,” he said, “we are investigating how we might manipulate this protein, or other proteins in the pathway, to treat disease.” 
Credit: Walter and Eliza Hall
Institute of Medical Research
New research suggests the Mcl-1 protein is crucial for the survival of natural killer (NK) cells and, therefore, innate immune responses.
Researchers deleted Mcl-1 from NK cells in mice and observed a loss of the cells from all tissues.
This made the mice more receptive to allogeneic hematopoietic stem cell transplants and resistant to toxic shock following a sepsis challenge, but it also made the mice susceptible to melanoma metastases.
The researchers believe their findings, published in Nature Communications, will help to determine how NK cells can be manipulated to treat a range of disorders.
They said Mcl-1 could be a target for boosting or depleting NK cell populations when necessary.
The researchers first discovered that Mcl-1 is highly expressed in NK cells. And Mcl-1 is regulated by IL-15 in a dose-dependent manner via STAT5 phosphorylation and subsequent binding to the 3′-UTR of Mcl-1.
“We showed Mcl-1 levels inside the cell increase in response to [IL-15],” said study author Nick Huntington, PhD, of the Walter and Eliza Hall Institute of Medical Research in Victoria, Australia.
“We previously knew IL-15 boosted production and survival of natural killer cells, and we have shown that IL-15 does this by initiating a cascade of signals that tell the natural killer cell to produce Mcl-1 to keep it alive.”
To further explore this phenomenon, the researchers deleted Mcl-1 from NK cells in mice and observed depletion of the cells in all tissues. The team said this was the result of a failure to antagonize pro-apoptotic proteins in the outer mitochondrial membrane.
Additional experiments showed that the mice needed the NK cells to fight off invading melanoma cells that had spread past the original cancer site.
“Without natural killer cells, the body was unable to destroy melanoma metastases that had spread throughout the body, and the cancers overwhelmed the lungs,” Dr Huntington said.
However, the loss of NK cells also made mice more receptive to allogeneic stem cell transplants and resistant to toxic shock after polymicrobial sepsis challenge.
“Natural killer cells led the response that caused rejection of donor stem cells in bone marrow transplantations,” Dr Huntington said. “They also produced inflammatory signals that can result in toxic shock syndrome, a potentially fatal illness caused by bacterial toxins that causes a whole-body inflammatory reaction.”
The researchers said these results clearly show a non-redundant pathway linking IL-15 to Mcl-1 in the maintenance of NK cells and innate immune responses.
Dr Huntington said the discovery provides a solid lead to look for ways of boosting or depleting NK cells when necessary.
“Now that we know the critical importance of Mcl-1 in the survival of natural killer cells,” he said, “we are investigating how we might manipulate this protein, or other proteins in the pathway, to treat disease.”
Credit: Walter and Eliza Hall
Institute of Medical Research
New research suggests the Mcl-1 protein is crucial for the survival of natural killer (NK) cells and, therefore, innate immune responses.
Researchers deleted Mcl-1 from NK cells in mice and observed a loss of the cells from all tissues.
This made the mice more receptive to allogeneic hematopoietic stem cell transplants and resistant to toxic shock following a sepsis challenge, but it also made the mice susceptible to melanoma metastases.
The researchers believe their findings, published in Nature Communications, will help to determine how NK cells can be manipulated to treat a range of disorders.
They said Mcl-1 could be a target for boosting or depleting NK cell populations when necessary.
The researchers first discovered that Mcl-1 is highly expressed in NK cells. And Mcl-1 is regulated by IL-15 in a dose-dependent manner via STAT5 phosphorylation and subsequent binding to the 3′-UTR of Mcl-1.
“We showed Mcl-1 levels inside the cell increase in response to [IL-15],” said study author Nick Huntington, PhD, of the Walter and Eliza Hall Institute of Medical Research in Victoria, Australia.
“We previously knew IL-15 boosted production and survival of natural killer cells, and we have shown that IL-15 does this by initiating a cascade of signals that tell the natural killer cell to produce Mcl-1 to keep it alive.”
To further explore this phenomenon, the researchers deleted Mcl-1 from NK cells in mice and observed depletion of the cells in all tissues. The team said this was the result of a failure to antagonize pro-apoptotic proteins in the outer mitochondrial membrane.
Additional experiments showed that the mice needed the NK cells to fight off invading melanoma cells that had spread past the original cancer site.
“Without natural killer cells, the body was unable to destroy melanoma metastases that had spread throughout the body, and the cancers overwhelmed the lungs,” Dr Huntington said.
However, the loss of NK cells also made mice more receptive to allogeneic stem cell transplants and resistant to toxic shock after polymicrobial sepsis challenge.
“Natural killer cells led the response that caused rejection of donor stem cells in bone marrow transplantations,” Dr Huntington said. “They also produced inflammatory signals that can result in toxic shock syndrome, a potentially fatal illness caused by bacterial toxins that causes a whole-body inflammatory reaction.”
The researchers said these results clearly show a non-redundant pathway linking IL-15 to Mcl-1 in the maintenance of NK cells and innate immune responses.
Dr Huntington said the discovery provides a solid lead to look for ways of boosting or depleting NK cells when necessary.
“Now that we know the critical importance of Mcl-1 in the survival of natural killer cells,” he said, “we are investigating how we might manipulate this protein, or other proteins in the pathway, to treat disease.”