Born to kill, natural killer cells are constantly on the prowl for potentially dangerous invaders, ready to unleash their deadly arsenal at a moment's notice. Prior to the study, scientists were familiar with the diverse repertoire of surface molecules that helps natural killer cells distinguish friend from foe, but how they acquired their reconnaissance tool kit had remained unclear.
"We suspected that an environmental signal triggered the differentiation of immature natural killer cells into cells that could recognize and kill invading pathogens," says one of the senior authors, Greg Lemke, Ph.D., a professor in the Salk's Molecular Neurobiology Laboratory, "but we didn't know what it was."
When co-senior author Claude Roth, Ph.D., an immunologist at the Institut Pasteur, discovered that low levels of a protein called Axl, which belongs to a class of molecules collectively known as receptor tyrosine kinases, correlated with diminished killer activity in natural killer cells, he turned to Lemke.
Lemke's lab had studied the effects of deleting or "knocking out" the Axl gene and its two cousins Mer and Tyro3, sometimes referred to as the Tyro3 family, for over a decade. Although the Salk scientists had been initially interested in how a missing Tyro3 protein impacted brain development, they found that mice lacking all three Tyro3 genes developed autoimmune diseases closely resembling the perplexing symptoms observed in human autoimmunity.
According to Lemke, they couldn't help noticing that the Tyro3 "knock-out" animals were very sick and prone to infections, which - now that we know that their natural killers were compromised - makes perfect sense. As part of the innate arm of the immune system, natural killer cells are the body's immediate line of defense, keeping invaders in check until T and B cells of the immune system, which take a few days to mobilize, kick into full gear.
Natural killer cells are armed with enzyme-filled sacs that spill their deadly contents when infected or cancerous cells cross the killer's path. In addition, they secrete cytokines, chemical messengers that jumpstart the T and B cell response.
What the Salk and Pasteur teams discovered is that when all three Tyro3 proteins are missing, natural killer cells are still armed with their arsenal of enzymes and cytokines, but they can't dip into their weapons cache because they lack the full spectrum of surface molecules that gives them the "license to kill".
"From these data it was clear that Tyro3 receptor kinases transmit the environmental signals, which we knew are crucial for the maturation of precursor cells," says Lemke. Receptor tyrosine kinases normally receive signals from a cell's environment and, upon activation, add a phosphate group to intracellular proteins, initiating a new repertoire of cellular behaviors.
For natural killer cells those signals - two well-established ligands of Tyro3 proteins called Gas6 and protein S - are secreted by bone marrow stromal cells, which form the local support network for natural killer cell precursors constantly generated in the bone marrow. As the immature natural killer cells get ready to move out of the bone marrow, stromal cells give them the go ahead to acquire the full spectrum of surface receptors, allowing them to attack with discrimination rather than raw determination.
In addition to Drs. Roth and Lemke, researchers contributing to this study include co-first author Anouk Caraux, Ph.D., and James P. Di Santo, Ph.D., both at the Institut Pasteur, Salk staff scientist and co-first author Qingxian Lu, Ph.D., Nadine Fernandez, Ph.D., formerly a postdoctoral researcher at the University of California at Berkeley and now at Laboratoire Français du Fractionnement et des Biotechnologies (LFB) in France, and David H. Raulet, Ph.D., a professor at the University of California at Berkeley.
The Salk Institute for Biological Studies in La Jolla, California, is an independent nonprofit organization dedicated to fundamental discoveries in the life sciences, the improvement of human health and the training of future generations of researchers. Jonas Salk, M.D., whose polio vaccine all but eradicated the crippling disease poliomyelitis in 1955, opened the Institute in 1965 with a gift of land from the City of San Diego and the financial support of the March of Dimes.