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 au

Contact: Karen Kreeger
University of Pennsylvania School of Medicine

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