Oct. 18, 2005
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 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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