Write your abstract here.Scientists provide insights into how the immune system avoids attacking itself.
finding
by University of Pennsylvania School of Medicine researchers
about how immune cells “decide” to become active or inactive may have
applications in fighting cancerous tumors, autoimmune diseases, and
organ transplant rejection. Pathology and Laboratory Medicine Professor
Gary A. Koretzky, MD, PhD, director of the Signal Transduction Program
at Penn’s Abramson Family Cancer Research Institute describes, in the
current issue of Nature Immunology, one way in which T cells may
develop
tolerance to host cells and proteins. Koretzky and colleagues
found that small fatty acids called diacylglycerols (DAGs), and the
enzymes that metabolize them, are critical players in the molecular
pathway that leads to activity versus inactivity.
Immune cells called T lymphocytes recognize invaders in the body, such
as viruses, bacteria, tumor cells, or allergens. Normally, T cells are
activated by a complex series of signals that end with the destruction
of the
foreign substance. However, some T cells are not activated, in
fact they are inactivated by a process called anergy or tolerance. This
process helps prevent immune cells from attacking themselves and other
normal cells and proteins.
“How T lymphocytes become activated or inactivated has been one of
the major questions in the field of immunology,” says senior author
Koretzky. “Our discovery shows that DAGs are critical for T-cell
activation so these cells can respond to foreign invaders. However,
when DAGs are chemically modified by enzymes called diacylglycerol
kinases, T cells become tolerant or unresponsive to foreign substances
and to self.”
The discovery was made by studying mice that had been engineered to
lack diacylglycerol kinases (DGKs). Although T cells from these
knock-out mice were normal in most respects the induction of tolerance
was impaired. When DAGs could not be chemically altered because the
DGKs were absent, the T cells were hyperreactive to foreign antigens
and could not be made tolerant to host cells.
Hyperreactivity was shown when purified T cells from DGK knockout
mice were stimulated by antigen in a culture dish. The failure of the T
cells to become tolerant was demonstrated in experiments where mice
were treated with a toxin from staphylococcal bacteria that should have
induced unresponsiveness. Instead, the T cells produced about five
times more of an immunity factor than did cells from normal mice.
The hyperreactive state, if controlled, might be beneficial to the
body under some circumstances; for example, some T cells might be made
more effective at eliminating tumors. The research team is continuing
to study DGK knock-out mice to see if they are more resistant to
tumors. If the hyper-reactive T cells in these mice recognize the tumor
cell as a foreign invader, then the tumor might be eliminated or
reduced. Conversely, if the tolerant state could be induced in a
controlled manner, it might benefit individuals with autoimmune disease
or help prevent rejection of transplants.
Source: University of Pennsylvania School of Medicine