Cytokine-mediated T cell activation

    Project: Research project

    Project Details

    Description

    DESCRIPTION (provided by applicant): Septic shock causes nearly 30% mortality and kills approximately 100,000 people every year in the United States alone. The high mortality rate associated with septic shock is due mainly to a "cytokine storm" that results in pulmonary edema, vascular leakage, organ failure, coma, and death. Although macrophages and monocytes are typically blamed for this condition, animal models suggest that cytokines produced by T cells also play a substantial role in this process. Virus-specific CD8+ T cells often avoid causing severe immunopathology by strictly regulating their cytokine production and turning cytokine secretion on, off, and on again in response to direct antigen contact. In contrast, interleukin-12 (IL-12) and interleukin-18 (IL-18) represent two potent inflammatory cytokines that trigger interferon-gamma (IFNg) production by activated T cells in the absence of direct antigen contact. Although activated CD8+ T cells are known to respond to IL-12/IL-18 stimulation, the effects of these cytokines on long-term, resting memory T cells is largely unknown and represents a significant gap in our understanding of this phenomenon. In our proposed studies, we will compare and contrast effector and memory T cells of a defined specificity in terms of: 1) cytokine production, 2) cytolytic activity, 3) proliferation, and 4) global gene expression following stimulation with IL-12 and IL-18. This information will be important for understanding how IL-12/IL-18 secretion might be used by infected cells as an intrinsic "danger" signal to trigger antimicrobial immune responses by nearby antigen-experienced T cells without requiring direct TcR stimulation. On the other hand, this loss of antigen specificity also appears to play a substantial role in certain types of T cell-mediated immunopathology associated with secondary bacterial infections and septic shock. For these reasons, a thorough understanding of cytokine-mediated T cell activation is critical for learning how to maintain or augment appropriate T cell responses while at the same time decreasing T cell-associated symptoms of disease.
    StatusFinished
    Effective start/end date4/1/043/31/10

    Funding

    • National Institutes of Health: $316,025.00
    • National Institutes of Health: $322,145.00
    • National Institutes of Health: $339,750.00
    • National Institutes of Health: $331,767.00
    • National Institutes of Health: $339,750.00

    ASJC

    • Medicine(all)
    • Immunology and Microbiology(all)

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