University Of Iowa Researchers Investigate Regulation Of Immune System Memory

University of Iowa researchers, led by John Harty, Ph.D., associate professor of microbiology, are making progress in understanding how these complicated aspects of the immune response are controlled. The UI team has found that two molecules, perforin and interferon gamma, already known to participate in the fight against infections, are also responsible for regulating the size and nature of both the initial immune response and the residual protective immunity. The research findings were published in the Nov. 17 issue of the journal Science. The lead author, Vladimir P. Badovinac, Ph.D., and co-author Amy R. Tvinnereim, Ph.D., are both postdoctoral fellows in Harty's lab.

"It was thought that the only role for these molecules was to enable T cells to directly or indirectly destroy infected cells," Harty said. "We have identified another role for the molecules, as regulators that control how many T cells are generated in response to infection and how many of these cells survive and contribute to immune memory."

Harty added that this work reinforces a long-standing notion about the immune system, that it is able to use the same molecule for different functions.

"The immune system has learned to use and modify existing systems to do the jobs required to fight off infections," Harty said.

When an active immune system is confronted by a new foreign invader such as bacteria or a virus, it initially generates large numbers of T cells specific for the infectious agent. These expanded cells undergo a process known as differentiation and become cells that can actively fight off infection. Once the infection is cleared, the majority of the expanded cells die off. The surviving 10 percent are maintained as memory cells.

"This death stage is very important because there are only so many cells that constitute the immune system. If you maintained all the expanded cells from each encounter with a pathogen you would rapidly use up your allotment of immune cells," Harty explained. "The precise regulation of the death phase after the expansion allows us to respond to many different pathogens without exhausting our immune system."

Until very recently, researchers evaluating the nature and strength of an immune response focused on antibody production. Antibodies are molecules generated by the immune system to help fight infection. They are easy to detect and quantify. In the last five years, however, there has been a revolution in scientists' ability to identify, count and assess the function of antigen-specific T cells with high precision. Measuring these cells gives a much more accurate assessment of an immune response to either an infection or a vaccine.

"I suspect that in the next few years we will be able to use these tools to assess how good human vaccines actually are," Harty said.

In the current studies, Harty and his colleagues used these measuring techniques and previous research to set about carefully measuring the levels of T cells during different stages of infection. Investigating the immune response in mice, genetically engineered to lack either or both molecules, the researchers elucidated the regulatory roles of perforin and interferon gamma.

The mice were infected with Listeria monocytogenes, a bacterial pathogen that causes food-borne infections in humans. The studies showed that perforin controls the total number of T cells initially generated in response to a pathogen, and interferon gamma controls the process by which most of those cells are eliminated after the infection is cleared. Interferon gamma also affects which parts of the pathogen cause the immune system to respond.

The roles of these molecules did not change when the researchers repeated the experiments using a virus as the infecting agent even though viruses and bacteria interact with the host animal in very different ways during an infection.

"This is very basic research aimed at understanding how this very precisely orchestrated expansion and decline, and memory phase of the immune system is controlled," Harty said. "Understanding how the basic biology of the system is regulated provides insight into how we might manipulate the system. In the case of these studies, the ultimate goal would be to learn how to manipulate the levels of T cell memory, which could result in better, more effective vaccinations."

Autoimmune diseases result from inappropriate activation of certain T cell subsets, which recognize self-antigens as opposed to pathogen antigens. Understanding how T cells are regulated could also help scientists understand and possibly treat autoimmune conditions.

Funding for this research was provided by the National Institutes of Health.