Differential sensitivity to Itk kinase signals for T helper 2 cytokine production and chemokine-mediated migration.
Allergic asthma is dependent on chemokine-mediated Th2 cell migration and Th2 cytokine secretion into the lungs. The inducible T cell tyrosine kinase Itk regulates the production of Th2 cytokines as well as migration in response to chemokine gradients. Mice lacking Itk are resistant to developing allergic asthma. However, the role of kinase activity of Itk in the development of this disease is unclear. In addition, whether distinct Itk-derived signals lead to T cell migration and secretion of Th2 cytokines is also unknown. Using transgenic mice specifically lacking Itk kinase activity, we show that active kinase signaling is required for control of Th2 responses and development of allergic asthma. Moreover, dominant suppression of kinase Itk activity led to normal Th2 responses, but significantly reduced chemokine-mediated migration, resulting in prevention of allergic asthma. These observations indicate that signals required for Th2 responses and migration are differentially sensitive to Itk activity. Manipulation of Itk's activity can thus provide a new strategy to treat allergic asthma by differentially affecting migration of T cells into the lungs, leaving Th2 responses intact.
Sahu
Nisebita
N
Center for Molecular Immunology & Infectious Disease, The Pennsylvania State University, University Park, PA 16802, USA.
Mueller
Cynthia
C
Fischer
Angela
A
August
Avery
A
D000485:Allergens / Q000008:administration & dosage; D000818:Animals; D001249:Asthma / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D016535:Bronchial Hyperreactivity / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D018925:Chemokines / Q000502:physiology*; D002634:Chemotaxis, Leukocyte / Q000235:genetics / Q000276:immunology*; D016207:Cytokines / Q000096:biosynthesis*; D018836:Inflammation Mediators / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology; D017434:Protein Structure, Tertiary / Q000235:genetics / Q000502:physiology; D011505:Protein-Tyrosine Kinases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D018418:Th2 Cells / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism / Q000473:pathology
D000485:Allergens; D018925:Chemokines; D016207:Cytokines; D018836:Inflammation Mediators; D010047:Ovalbumin; D011505:Protein-Tyrosine Kinases; C080813:emt protein-tyrosine kinase