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    Inhibition of Mammalian T cells by <italic>Salmonella enterica</italic> serovar Typhimurium

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    StonyBrookUniversityETDPageEmbargo_20130517082608_116839.pdf (40.31Kb)
    Date
    1-Dec-12
    Author
    Kullas, Amy Laura
    Publisher
    The Graduate School, Stony Brook University: Stony Brook, NY.
    Metadata
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    Abstract
    Bacterial pathogens must avoid clearance by the immune system to establish infection, yet many processes of bacterial immune subversion remain undefined. T cells are a key component of the mammalian immune system and are required for protective immunity against many bacterial pathogens. Salmonella enterica serovar Typhimurium avoid clearance by the host immune system by suppressing T cell responses, yet the mechanisms mediating this immunosuppression are still unknown. We show that S. Typhimurium inhibit T cell responses by producing L-asparaginase II, which catalyzes the hydrolysis of L-asparagine to aspartic acid and ammonia. L-asparaginase II is necessary and sufficient to suppress T cell blastogenesis, cytokine production and proliferation, and to down-modulate expression of the T cell receptor (TCR). Purified L-asparaginase II alters TCR levels and cytokine profiles of T cells in vitro. Furthermore, S. Typhimurium-induced inhibition of T cells in vitro is prevented upon addition of L-asparagine. S. Typhimurium lacking the L-asparaginase II gene (STM3106) are unable to inhibit T cell responses and exhibit attenuated virulence in vivo. L-asparaginases are used to treat acute lymphoblastic leukemia through mechanisms that likely involve amino acid starvation of leukemic cells and these findings indicate that pathogens similarly use L-asparagine depravation to limit T cell responses.
    Description
    160 pg.
    URI
    http://hdl.handle.net/1951/60266
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    • Stony Brook Theses & Dissertations [SBU] [1955]

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