Notch signaling molecule important in type 2 immunity

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Notch signaling molecule important in type 2 immunity

(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 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 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. "