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The Tec Family Kinase, IL-2-Inducible T Cell Kinase, Differentially Controls Mast Cell Responses¹

Archana S. Iyer^*, and Avery August^2,*,

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

The Tec family tyrosine kinase, IL-2-inducible T cell kinase (Itk), is expressed in T cells and mast cells. Mice lacking Itk exhibit impaired Th2 cytokine secretion; however, they have increased circulating serum IgE, but exhibit few immunological symptoms of allergic airway responses. We have examined the role of Itk in mast cell function and FcRI signaling. We report in this study that Itk null mice have reduced allergen/IgE-induced histamine release, as well as early airway hyperresponsiveness in vivo. This is due to the increased levels of IgE in the serum of these mice, because the transfer of Itk null bone marrow-derived cultured mast cells into mast cell-deficient W/W^v animals is able to fully rescue histamine release in the W/W^v mice. Further analysis of Itk null bone marrow-derived cultured mast cells in vitro revealed that whereas they have normal degranulation responses, they secrete elevated levels of cytokines, including IL-13 and TNF-, particularly in response to unliganded IgE. Analysis of biochemical events downstream of the FcRI revealed little difference in overall tyrosine phosphorylation of specific substrates or calcium responses; however, these cells express elevated levels of NFAT, which was largely nuclear. Our results suggest that the reduced mast cell response in vivo in Itk null mice is due to elevated levels of IgE in these mice. Our results also suggest that Itk differentially modulates mast cell degranulation and cytokine production in part by regulating expression and activation of NFAT proteins in these cells.

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 National Institutes of Health Grants AI051626 and AI065566 to A.A. The Center for Molecular Immunology & Infectious Disease is supported in part by a grant from the Pennsylvania Department of Health.

² Address correspondence and reprint requests to Dr. Avery August, Center for Molecular Immunology & Infectious Disease, Department of Veterinary & Biomedical Sciences, Pennsylvania State University, 115 Henning Building, University Park, PA 16802. E-mail address: axa45{at}psu.edu

³ Abbreviations used in this paper: AHR, airway hyperresponsiveness; BMMCs, bone marrow-derived cultured mast cells; Btk, Bruton’s tyrosine kinase; HSA, human serum albumin; Itk, IL-2-inducible T cell kinase; PLC, phospholipase C; WT, wild type.