When you get an acute infection, such as
influenza, the body generally responds with a coordinated response
of immune-cell proliferation and attack that rapidly clears the
pathogen. Then, their mission done, the immune system stands down,
leaving a population of sentinel memory cells to rapidly redeploy
the immune system in the event of reinfection.
This is why vaccination works, and it’s
why, in theory at least, people who have had the chicken pox once
will never get it again.
But what about chronic infection? In the
case of such pathogens as hepatitis C, HIV, and malaria, the body
and the pathogen essentially fight to a prolonged stalemate, neither
able to gain an advantage. Over time, however, the cells become
“exhausted” and the immune system can collapse, giving the pathogen
the edge.
Now, a new study by researchers at the
Perelman School of Medicine, University of Pennsylvania, is showing
just how that happens. The findings also suggest a novel
therapeutical approach that might be used to shift the balance of
power in chronic infections.
The team, led by E. John Wherry, PhD,
associate professor of Microbiology and Director of the Institute
for Immunology, used a mouse model of chronic viral infection to map
the T-cell response that arises when the immune system is on an
extended war footing. They found that two distinct classes of
virus-specific CD8+ T cells – one expressing high levels of the
protein T-bet, the other expressing high levels of the protein
Eomes, work together to keep the infection in check.
Specifically, they found that the two
cell populations appear to have a progenitor-mature cell
relationship. The T-bet-expressing cells appear to function as the
progenitor cells – that is, stem cells. These cells divide both to
regenerate and maintain the pool of virus-specific T cells. But they
also divide and differentiate to form mature, terminally
differentiated Eomes-expressing cells. These cells are more
effective at fighting the virus itself, but cannot replicate.
“There’s a balance, an equilibrium,
which allows you to maintain control over the infection but is
insufficient to give you complete clearance,” Wherry explains.
These two cell subpopulations tend to
confine themselves to different anatomic regions in the infected
animals, the researchers found. T-bet-positive cells were found in
the blood and spleen, whereas Eomes cells were found in the liver,
bone marrow, and gut.
Loss of either subpopulation, which the
researchers modeled by deleting one or the other protein, reduces
the immune system’s ability to fight the infection, leading to a
shift in favor of the pathogen.
According to Wherry, these data can help
explain the gradual loss of virus-specific T cells observed in such
chronic infections as hepatitis C.
“Our data suggest the reason for loss of
immune control during some chronic infections is that the long-term
pressure on this progenitor-mature cell relationship depletes the
progenitor pool,” he says.
What’s more, the study suggests new
therapeutic avenues that can be used to fight, or at least better
control, chronic infections. For instance, he says, “If we can
maintain these progenitor cells longer, or coax the terminal progeny
to divide further, we may be able to shift the balance and maintain
control of the infection,” he says.
Wherry’s lab is now studying candidate
molecular pathways to determine their efficacy in controlling, and
perhaps modulating, these two T-cell populations.
Penn authors include Michael A. Paley,
Pamela M. Odorizzi, Jonathan B. Johnnidis, Douglas V. Dolfi, Burton
E. Barnett.
The study was funded by National
Institutes of Health grants T32-AI-07324; AI0663445; AI061699;
AI076458; AI083022, AI078897, HHSN266200500030C; AI082630, and the
Dana Foundation and appears in the November 30 issue of Science.
For more information
http://www.uphs.upenn.edu/news/
(MDN) |