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    The Function of the Tyrosine Kinase, Itk, in CD4+ T Cell Differentiation and Death: a Dissertation

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    Authors
    Miller, Andrew Todd
    Faculty Advisor
    Dr. Leslie J. Berg
    Academic Program
    Immunology and Microbiology
    UMass Chan Affiliations
    Pathology
    Document Type
    Doctoral Dissertation
    Publication Date
    2003-07-31
    Keywords
    CD4-Positive T-Lymphocytes
    Immunity
    Cellular
    Protein-Tyrosine Kinase
    Amino Acids, Peptides, and Proteins
    Animal Experimentation and Research
    Cells
    Enzymes and Coenzymes
    Hemic and Immune Systems
    
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    Abstract
    The Tec family tyrosine kinase, Itk, plays an important role in signal transduction following T cell receptor engagement. Several prior studies have established the importance of Itk in immune system processes, such as T cell development and T cell activation. Additional biochemical studies have found that Itk specifically functions within a multi-molecular signalosome complex, which ultimately functions to provide a platform by which Itk can phosphorylate and activate PLC-γ1, a crucial step in T cell activation. To further study how Itk regulates distinct immune outcomes via T cell effector processes within the peripheral immune system, and to further understand how Itk functions in T cells in response to a physiological ligand-receptor interaction, I crossed Itk-deficient mice to mice transgenic for a TCR specific for a moth cytochrome C peptide. My studies have established a unique role for Itk in several important aspects of T cell function. Following T cell activation, I identified an imperative role for Itk in activation-induced cell death via FasL, a mechanism of immune homeostasis. Furthermore, I found Itk plays a unique role in the process of T cell differentiation, where Itk positively regulates the induction of cytokine genes, such as IL-4, while negatively regulating the induction of T-bet, a transcription factor important for Th1 differentiation. Lastly, following T cell differentiation, I found that Itk mRNA and protein are up-regulated during Th2 differentiation, while Rlk, a related Tec kinase, disappears rapidly from Th2 cells, indicating a critical role for Itk in Th2 cell function. Collectively, my thesis work has more clearly defined an important function for Itk not only in TCR signaling, but also in immune processes such as T cell differentiation and activation-induced cell death that are required for proper immune function.
    DOI
    10.13028/2jm2-2156
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/31923
    Rights
    Copyright is held by the author, with all rights reserved.
    ae974a485f413a2113503eed53cd6c53
    10.13028/2jm2-2156
    Scopus Count
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    Morningside Graduate School of Biomedical Sciences Dissertations and Theses

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