(Philadelphia, PA) - A 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 online
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
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
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.
This work was funded by a grant from the National Institutes of
Health and the support of the Abramson Family Cancer Research Institute.
Co-authors, in addition to Koretzky, are Benjamin A. Olenchock and
Martha Jordan from Penn, as well as Rishu Guo, Jeffery H. Carpenter,
and Xiao-Ping Zhong from Duke University Medical Center and Matthew
K. Topham from the University of Utah.
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