(Philadelphia, PA) - Defects in immune system
cells called T helper cells may lead to diseases characterized by
a faulty inflammatory response such as autoimmunity and asthma.
Understanding the molecular steps involved in how T helper cells
mature may help researchers develop treatments for these diseases.
Helper T cells differentiate into two different types of cells -Th1
or Th2 - which are responsible for regulating immunity to different
types of pathogens. Now, researchers at the University of
Pennsylvania School of Medicine have shed light on a key
molecular switch in this differentiation.
is a protein that is a critical regulator of the process by which
stem and other multipotent cells take on a specialized function,
such as a T lymphocyte or a nerve cell in organisms ranging from
fruitflies to humans. Using mice in which Notch signaling could
be induced to turn off in mature T cells, the researchers showed
that Notch signaling is an important determinant of whether an organism
can mount an effective Th2 response. The mice lacking Notch signaling
were unable to mount a protective Th2 cell response against infection
by the gastrointestinal parasitic worm Trichuris muris.
However, the mice did mount a healthy Th1 response to an infection
by the intracellular parasite Leishmania major, showing
that Notch signaling is specifically required for the Th2 arm of
the immune system.
These findings indicate that regulating Notch signaling may have
a therapeutic role in treating diseases caused by abnormally increased
Th2 responses, such as asthma, autoimmunity, and some forms of inflammatory
bowel disease. Drugs that inhibit Notch signaling, called gamma
secretase inhibitors, are currently in clinical trials for T-cell
leukemia and Alzheimer's disease. This study - published in today’s
issue of the Journal of Experimental Medicine - suggests
that these drugs may be useful in treating diseases typified by
increased Th2 responses.
Senior author Warren Pear, MD, PhD, Associate Professor
of Pathology and Laboratory Medicine, was one of the original discoverers
of the role of Notch signaling in T-cell development. Notch activates
gene transcription in the nucleus of cells, and depending on the
biochemical context, it turns certain pathways on and others off.
“The potential importance of our study is that it shows that
Notch signaling specifically influences Th2 immunity in a live animal
when challenged with a pathogen, suggesting that drugs that inhibit
Notch may be useful for treating diseases associated with a pathological
Th2 response, such as asthma,” says Pear. He is also a member
of Penn's Abramson Family Cancer Research Institute
and The Institute for Medicine and Engineering.
Helper T cells fight many types of infectious diseases and are also
the cells that regulate tolerance to self and the molecules that
cause the pathogenesis of such inflammatory diseases as arthritis,
inflammatory bowel disease, and asthma. Antigen-presenting cells
take up pathogens and migrate to the spleen or lymph nodes, where
they instruct immature T cells how to differentiate into Th1 or
Th2 helper T cells, killer T cells, or other types of immune system
Some of the factors that signal a T cell to become Th1 or Th2 cells
are well characterized, but some are not. “The role of Notch
in that decision-making has been controversial,” says co-author
Terry Fang, a graduate student in Penn’s
Immunology Program. “And this paper weighs in on this.”
Some studies suggest that Notch is important for the Th1 pathway,
others suggest both Th1 and Th2. This study suggests that there's
a specific requirement for Notch in Th2 differentiation only.
The specificity of Notch in regulating T-cell function is highlighted
in this study. “Mice lacking Notch failed to control infection
with a pathogen requiring a Th2 response, demonstrating that Notch
is a critical regulator of this response,” adds co-author
David Artis, PhD, Assistant Professor at Penn’s
School of Veterinary Medicine. “The ability of these same
animals to mount strong Th1 responses demonstrates the specificity
of the Notch pathway in regulating this important cell type of the
The potential clinical benefit of these new findings is that gamma
secretase inhibitors may so on be available for testing in the clinics.
One potential side effect of these drugs is that they inhibit other
pathways besides Notch. In addition, inhibiting Notch may cause
side effects because this protein is used in a wide variety of cellular
processes. The new mouse model described in this paper may be particularly
useful for identifying the consequences of turning Notch off in
different organs, an important issue for assessing potential side
effects of pharmacologic Notch inhibitors.
The current work provides the rationale for determining whether
manipulating Notch signaling will be useful in combating such diseases
as parasitic infections, asthma, and inflammatory bowel disease.
“The exciting possibility is that therapies are available,”
says Pear. “The challenge, however, is determining their efficacy
In addition to Pear, Fang, and Artis, study co-authors are: LiLi
Tu, Olga Shestova, Seth E. Pross, and Ivan Maillard, all from Penn.
This study was funded by the National Institutes of Health, the
Leukemia and Lymphoma Society, the Crohn’s and Colitis Foundation
of America’s William and Shelby Modell Family Foundation Research
Award, the Cancer Research Institute, and the Damon Runyon Cancer
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