CONTACT: JENNIFER BROWN
Iowa City IA 52242
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Release: EMBARGOED UNTIL 1pm (CST) NOV. 16, 2000
Nov. 16, 2000
UI researchers investigate regulation of immune system memory
IOWA CITY, Iowa -- If a person's immune system successfully fights off an
infection, not only does that person recover, but they also acquire immunity
against re-infection by that same pathogen. The ability of the immune system
to remember pathogens it has already defeated, and to respond rapidly and
effectively to them during future exposures, is the basis of vaccination strategies.
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
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.
University of Iowa Health Care describes the partnership between
the UI College of Medicine and the UI Hospitals and Clinics and the patient
care, medical education and research programs and services they provide.