Penn Researchers Provide Insights
into How the Immune System Avoids Attacking Itself
Discovery May Have Applications in Cancer Biology and Autoimmune
(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 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
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.
PENN Medicine is a $2.9 billion enterprise dedicated
to the related missions of medical education, biomedical research, and
high-quality patient care. PENN Medicine consists of the University of
Pennsylvania School of Medicine (founded in 1765 as the nation's first
medical school) and the University of Pennsylvania Health System.
Penn's School of Medicine is ranked #2 in the nation for receipt of NIH research funds; and ranked #3 in the nation in U.S. News & World Report's most recent ranking of top research-oriented medical schools. Supporting 1,400 fulltime faculty and 700 students, the School of Medicine is recognized worldwide for its superior education and training of the next generation of physician-scientists and leaders of academic medicine.
The University of Pennsylvania Health System includes three hospitals, all of which have received numerous national patient-care honors [Hospital of the University of Pennsylvania; Pennsylvania Hospital, the nation's first hospital; and Penn Presbyterian Medical Center]; a faculty practice plan; a primary-care provider network; two multispecialty satellite facilities; and home care and hospice.