Notch Signaling Molecule Important in Type 2 Immunity
Findings May Lead to New Treatments for Asthma and Other
(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.
Notch 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 cells.
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
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 immune system.”
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 and safety.”
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 Research Foundation.
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