|
Report:
Immune defenses never
forget antigen
Investigator: Peter
Doherty
Thursday Jul
26th, 2001
by Julie Clayton
The "memory" of
a virus infection - a phenomenon that supplies a rapid reaction force in
the immune system ready to eliminate the same virus at the next encounter -
can last a lifetime without the need for a "top-up" encounter.
The claim, backed by new data presented today, contradicts immunological
dogma.
"Immunologists seem to believe in mythology," said Peter
Doherty, of the St. Jude Children's Research Hospital in Memphis,
Tennessee. "Once embedded in the literature there seems to be no way
of getting rid of it," he told BioMedNet News.
The findings directly challenge a scientific dogma that has arisen over
the past two decades. The dogma states that to keep alive a vital stock of
"memory" T cells - the arm of the immune system that targets
pathogens in an exquisitely specific manner - the T cells need somehow to
continue to "see" a fragment of their target antigen, stored
somewhere in the body.
Nobel prizewinner Rolf Zinkernagel, of the Institute for Experimental
Immunology in Zurich, is a particular champion of the antigen persistence
idea.
This idea proposes that fragments of virus may be sequestered away in
the lymph nodes. Here, memory T cells with the ability to kill
virus-infected cells, called CD8 T cells, are likely to
"traffic-through" and receive a "top-up" stimulus with
their specific antigen. Zinkernagel's data derive from a mouse model of
virus infection, with the lymphocyte choriomeningitis virus, or LCMV.
But Doherty, who shared the Nobel prize with Zinkernagel for joint work
they performed in the 1970s, has since developed a mouse model for
infection with influenza virus, with quite different results.
Doherty now reports that rather than expand and die rapidly, after
beating off a viral infection, influenza-specific CD8 memory T cells
persist for a far longer time than previously thought. Most significantly,
Doherty says, this is after the the virus has been completely eliminated,
with no fragments remaining.
"There's a lot of stuff embedded in the literature about this
that's wrong, but it's become paradigms. For example, the idea that most
(90 or 98% of) T cells die after the acute response doesn't seem to be
right. But you keep seeing this idea over and over again," he said.
Using more precise measures of T cell numbers than were previously
available, Doherty has discovered that more memory T cells survive than
originally thought. But what keeps them alive is a highly contentious
issue.
"In the Proceedings of the National Academy of Sciences we
reported that if you look at a whole mouse rather than just a selected
site, the number of cells in the site of virus growth falls quickly, but
elsewhere the numbers fall more slowly. But there seems to be no way of
getting this message across," Doherty said.
Jonathan Sprent, of the Scripps Institute for Research in La Jolla,
California, reported to the same audience that chemical signals, in the
form of the cytokine IL15, are sufficient to keep CD8 memory T cells alive.
He showed that many cells of the immune system are likely to release
IL15 in vitro, but "what makes it under normal physiological
conditions is unclear, although it maybe dendritic cells" he told BioMedNet
News.
Dendritic cells, in turn, are usually stimulated by the presence of
invading pathogens, and represent a link between first-line defenses and
the longer-term T cell response to antigens. But a direct link between
bacterial infection and the maintenance of T cell memory remains to be
seen.
The important feature, according to Sprent, is that memory T cells are
highly sensitive to stimulation by cytokines.
Doherty also questions the origin of memory T cells - whether they arise
from cells that are simply dividing as a result of an encounter with a
virus antigen, or whether they arise from T cells that have developed
beyond this cell division stage to become differentiated "killer"
T cells, which destroy virus-infected cells.
"The idea that effector cells become memory cells is almost
certainly wrong. It's the activated T cell that becomes a memory
cell," he told BioMedNet News. "I think we're getting a
much better understanding of what a memory T cell is," he concluded.
|
