AMASSING AN ARMY: Killer T cells are the body's sharpshooters, which are recruited to help fight a specific infection. But until now, researchers didn't know what determined the ultimate size of the specialized forces. Image: SCIENCE/AAAS
When the body contracts a new virus or bacteria, specific white blood cells—T lymphocytes—are recruited to fight back. Each T cell is only programmed, however, to recognize a specific viral or bacterial strain, so out of every 100,000 T cells, only one might match a novel pathogen. Therefore, once the matches are found, those few cells need to multiply in a hurry to stave off illness.
Up to now researchers have been unsure to what extent the strength of the body's immune response was due to the number of these T cells initially recruited from lymph nodes (clonal selection) and to what extent is was cause by the amount that those T cells multiplied (clonal expansion). "The basic question is: How is the strength of the response regulated?" explains Ton Schumacher, a professor in the department of immunology at The Netherlands Cancer Institute in Amsterdam.
Schumacher and a team of researchers report online in Science today that it is T cell expansion that drives the immune system response more than their selection. "The striking finding is that in essentially all conditions the number of T cells recruited is constant," Schumacher says. "The magnitude of the response is [the result of] the subsequent expansion."
Previously, researchers were unable to answer the question because, as Schumacher notes, "we really had no way of measuring the diversity in T cell response." So, in an effort to trace the "kinship" of T cells, the researchers used unique DNA bar codes to tag and follow individual T cells and their progeny in lab mice. They found that regardless of the nature of the infection, the number of T cells initially recruited was constant, but the number of cells that each T cell went on to spawn varied in number, fingering the primary role of clonal expansion—rather than selection—in the immune response level.
The expansion finding can now help researchers better understand how the immune system works and find ways to enhance it. For instance, vaccine-makers and other researchers now have a more defined target for their experiments. "We don't have to bother with the selection phase," Schumacher says, "but the expansion phase is where we should focus our efforts."
The genetic marking method also paves the way for other important medical research. Using cell kinship or "paternity" tracking, future researchers could study stem cells to see how they divide and differentiate from each other, aiding in efforts to create therapies that introduce self-renewing stem cells into damaged tissue to differentiate into specific tissue types and treat disease and injuries.
Learning more about how the immune system responds can also help researchers get to the bottom of autoimmune diseases. Adam Adler, an associate professor at the Center for Immunotherapy of Cancer and Infectious Diseases at the University of Connecticut Health Center in Farmington who was not involved in the expansion study, says his lab is working on research to help understand how T cells discern between "self and not self," or native and foreign material. The researchers are examining the signals that tell T cells not to attack the body's own tissues and the process behind that cell deactivation, with the goal of discovering ways to manipulate the process to switch it off and on, he explains.
Aside from preventing or treating autoimmune disorders, such insights could also be turned on their head to fight cancerous tumors, which are often seen and treated by the immune system as harmless bodily tissue. "We'd like to trick the immune system into thinking it's a foreign tissue," Adler says.
For Schumacher, the new T cell discovery highlights the impressiveness of the body itself. "The most striking thing is how remarkably efficient the immune system is," he says. Because the rate of selecting T cells is so constant, Schumacher and his team think that the body is, indeed, consistently ferreting out the 10 T cells in a million that match up to a particular infection—within a matter of a few days.