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. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI054458-05
Application #
7387408
Study Section
Special Emphasis Panel (ZRG1-SSS-F (01))
Program Officer
Lapham, Cheryl K
Project Start
2004-04-01
Project End
2010-03-31
Budget Start
2008-04-01
Budget End
2010-03-31
Support Year
5
Fiscal Year
2008
Total Cost
$316,025
Indirect Cost
Name
Oregon Health and Science University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
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Raue, Hans-Peter; Slifka, Mark K (2007) Pivotal advance: CTLA-4+ T cells exhibit normal antiviral functions during acute viral infection. J Leukoc Biol 81:1165-75
Koguchi, Yoshinobu; Thauland, Timothy J; Slifka, Mark K et al. (2007) Preformed CD40 ligand exists in secretory lysosomes in effector and memory CD4+ T cells and is quickly expressed on the cell surface in an antigen-specific manner. Blood 110:2520-7
Beadling, Carol; Slifka, Mark K (2006) Quantifying viable virus-specific T cells without a priori knowledge of fine epitope specificity. Nat Med 12:1208-12

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