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Differential Sensitivity to Itk Kinase Signals for T Helper 2 Cytokine Production and Chemokine-Mediated Migration¹

Nisebita Sahu^*,, Cynthia Mueller^2,*, Angela Fischer^* and Avery August^3,*

^* Center for Molecular Immunology & Infectious Disease and Department of Veterinary and Biomedical Sciences and Department of Biochemistry & Molecular Biology, The Pennsylvania State University, University Park, PA 16802

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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Grants AI051626 and AI065566 from the National Institutes of Health, and from the American Heart Association (to A.A.).

² Current address: Department of Biomedical Sciences, Cornell University, School of Veterinary Medicine, Ithaca, NY 14850.

³ Address correspondence and reprint requests to Dr. Avery August, Center for Molecular Immunology & Infectious Disease, Department of Veterinary and Biomedical Sciences, 115 Henning Building, The Pennsylvania State University, University Park, PA 16802. E-mail address: axa45{at}psu.edu

⁴ Abbreviations used in this paper: AHR, airway hyperresponsiveness; SRF, serum response factor; BALF, bronchoalveolar lavage fluid; SH, Src homology; WT, wild type.