Defects in immune system cells called T helper cells may leadto diseases characterized by a faulty inflammatory response such asautoimmunity and asthma. Understanding the molecular steps involved inhow T helper cells mature may help researchers develop treatments forthese diseases.
Helper T cells differentiate into two differenttypes of cells –Th1 or Th2 – which are responsible for regulatingimmunity to different types of pathogens. Now, researchers at theUniversity of Pennsylvania School of Medicine have shed light on a keymolecular switch in this differentiation.
Notch is a protein thatis a critical regulator of the process by which stem and othermultipotent cells take on a specialized function, such as a Tlymphocyte or a nerve cell in organisms ranging from fruitflies tohumans. Using mice in which Notch signaling could be induced to turnoff in mature T cells, the researchers showed that Notch signaling isan important determinant of whether an organism can mount an effectiveTh2 response. The mice lacking Notch signaling were unable to mount aprotective Th2 cell response against infection by the gastrointestinalparasitic worm Trichuris muris. However, the mice did mount a healthyTh1 response to an infection by the intracellular parasite Leishmaniamajor, showing that Notch signaling is specifically required for theTh2 arm of the immune system.
These findings indicate thatregulating Notch signaling may have a therapeutic role in treatingdiseases caused by abnormally increased Th2 responses, such as asthma,autoimmunity, and some forms of inflammatory bowel disease. Drugs thatinhibit Notch signaling, called gamma secretase inhibitors, arecurrently in clinical trials for T-cell leukemia and Alzheimer'sdisease. This study – published in today's issue of the Journal ofExperimental Medicine – suggests that these drugs may be useful intreating diseases typified by increased Th2 responses.
Seniorauthor Warren Pear, MD, PhD, Associate Professor of Pathology andLaboratory Medicine, was one of the original discoverers of the role ofNotch signaling in T-cell development. Notch activates genetranscription in the nucleus of cells, and depending on the biochemicalcontext, it turns certain pathways on and others off. "The potentialimportance of our study is that it shows that Notch signalingspecifically influences Th2 immunity in a live animal when challengedwith a pathogen, suggesting that drugs that inhibit Notch may be usefulfor treating diseases associated with a pathological Th2 response, suchas asthma," says Pear. He is also a member of Penn's Abramson FamilyCancer Research Institute and The Institute for Medicine andEngineering.
Helper T cells fight many types of infectiousdiseases and are also the cells that regulate tolerance to self and themolecules that cause the pathogenesis of such inflammatory diseases asarthritis, inflammatory bowel disease, and asthma. Antigen-presentingcells take up pathogens and migrate to the spleen or lymph nodes, wherethey instruct immature T cells how to differentiate into Th1 or Th2helper T cells, killer T cells, or other types of immune system cells.
Someof the factors that signal a T cell to become Th1 or Th2 cells are wellcharacterized, but some are not. "The role of Notch in thatdecision-making has been controversial," says co-author Terry Fang, agraduate student in Penn's Immunology Program. "And this paper weighsin on this." Some studies suggest that Notch is important for the Th1pathway, others suggest both Th1 and Th2. This study suggests thatthere's a specific requirement for Notch in Th2 differentiation only.
Thespecificity of Notch in regulating T-cell function is highlighted inthis study. "Mice lacking Notch failed to control infection with apathogen requiring a Th2 response, demonstrating that Notch is acritical regulator of this response," adds co-author David Artis, PhD,Assistant Professor at Penn's School of Veterinary Medicine. "Theability of these same animals to mount strong Th1 responsesdemonstrates the specificity of the Notch pathway in regulating thisimportant cell type of the immune system."
The potential clinicalbenefit of these new findings is that gamma secretase inhibitors may soon be available for testing in the clinics. One potential side effectof these drugs is that they inhibit other pathways besides Notch. Inaddition, inhibiting Notch may cause side effects because this proteinis used in a wide variety of cellular processes. The new mouse modeldescribed in this paper may be particularly useful for identifying theconsequences of turning Notch off in different organs, an importantissue for assessing potential side effects of pharmacologic Notchinhibitors.
The current work provides the rationale fordetermining whether manipulating Notch signaling will be useful incombating such diseases as parasitic infections, asthma, andinflammatory bowel disease. "The exciting possibility is that therapiesare available," says Pear. "The challenge, however, is determiningtheir 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 theNational Institutes of Health, the Leukemia and Lymphoma Society, theCrohn's and Colitis Foundation of America's William and Shelby ModellFamily Foundation Research Award, the Cancer Research Institute, andthe Damon Runyon Cancer Research Foundation.
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