Mouse Study Could Aid Vaccine Designers
Investigators from the National Institute of Allergy and Infectious
Diseases (NIAID), part of the National Institutes of Health, have
conducted studies in mice to gain a new picture of how the immune
system's "killer" T cells are prompted to destroy infected
cells. Their insights provide a blueprint for rational design of
vaccines that induce desired T-cell responses.
The findings are published in this week's Science. "If
we are correct, what we've found will put rational vaccine design
on a firmer footing," says Jonathan Yewdell, M.D., Ph.D., who
led the NIAID team.
T cells belong to the cellular arm of the immune system's two-pronged
defense mechanism against foreign invaders the other arm
features blood-borne antibodies. Historically, vaccines aimed to
stimulate antibody production in a bid to prevent specific diseases.
More recently, scientists have begun to manipulate T cells to create
vaccines effective against pathogens that antibodies alone cannot
control. Such T-cell-inducing vaccines are being tested against
infectious diseases such as HIV/AIDS and hepatitis and are being
studied as treatments for certain cancers.
Once alerted to the presence of infected cells, resting T cells
are "awakened" and begin to multiply rapidly. Then they
zero in on and destroy infected cells while sparing uninfected ones.
Rousing slumbering T cells is the job of dendritic cells, the sentinels
of the immune system. Dendritic cells activate the T cells by displaying
peptides small pieces of virus or other foreign protein
on their surfaces. In a process called direct priming, dendritic
cells generate these peptides by themselves after being infected
by a virus. Alternatively, dendritic cells may first interact with
other body cells that have been infected by a virus and then activate
the T cells. This indirect route is called cross-priming.
Vaccines may exploit either route to T-cell priming, but scientists
have not known enough about the mechanisms behind cross-priming
to exploit this route in vaccine design.
Test tube experiments suggested that molecular "chaperones"
accompany peptides from infected cells to dendritic cells, and a
number of experimental vaccines have been designed on this premise.
But few studies have been done to determine if chaperoned peptides
play any role in animal systems, notes Dr. Yewdell.
If the chaperoned peptide theory is correct, infected cells that
make the most peptides should most strongly stimulate cross-priming.
Conversely, fewer peptides should mean less cross-priming. To test
this prediction, Dr. Yewdell and his colleagues created virus-infected
cells that were genetically or chemically prevented from producing
peptides and injected those cells into mice. They found the opposite
of what they expected: cross-priming correlated directly with levels
of whole proteins, rather than levels of peptides, expressed by
the virus-infected cells.
This new information could aid vaccine design, says Dr. Yewdell.
"Our experiments indicate that two distinct pathways exist
to prime T cells," he says. If the rules for T-cell priming
suggested by these experiments are correct, vaccines meant to interact
with dendritic cells should be designed to generate large amounts
of peptides, while vaccines that target other kinds of cells should
be designed to generate whole proteins that will go on to be processed
in the dendritic cells during T-cell cross-priming.
Prompting a strong and specific T-cell reaction may be the key
to vaccines that are effective against certain infectious diseases,
including HIV/AIDS and malaria, notes Dr. Yewdell. It is also possible
that a therapeutic vaccine might be developed to boost the T cell
activity of people who have chronic liver infections caused by hepatitis
B or C viruses.
NIAID is a component of the National Institutes of Health, an agency
of the U.S. Department of Health and Human Services. NIAID supports
basic and applied research to prevent, diagnose and treat infectious
diseases such as HIV/AIDS and other sexually transmitted infections,
influenza, tuberculosis, malaria and illness from potential agents
of bioterrorism. NIAID also supports research on transplantation
and immune-related illnesses, including autoimmune disorders, asthma
Press releases, fact sheets and other NIAID-related materials
are available on the NIAID Web site at http://www.niaid.nih.gov.
Reference: CC Norbury et al. CD8+ cell cross-priming
via transfer of proteasome substrates. Science 304:1318-21