The overall goal of this project is to examine a regulatory mechanisms that limits the function of inflammatory T cells, specifically cytotoxic T cells (CTL). The hypothesis will be examined that components released from lysing cells may be involved in T cell regulation by providing a substrate for an ecto-enzyme present on T cells. Among the possible substrates, NAD is one which is abundant inside cells but its extracellular concentration is exceedingly low. Support for the notion that NAD may play a regulatory role in CTL function is the presence of enzymes that split NAD leading to a posttranslational modification of arginines in proteins, known as mono-ADP-ribosylation. Concomitantly various CTL functions are found to be inhibited. We propose to explore how mono-ADP-ribosylation of cell surface molecules on lymphocytes, regulates their function. The expression of cell surface ADP- ribosyltransferase (ADPRT) on lymphocyte classes will be assayed and correlated with inhibitory effects of NAD. To elucidate the precise mechanisms responsible for this regulatory circuit, experiments are proposed to identify the cell surface proteins which are modified. Preliminary experiments suggest that the modification affects co- receptors and that this causes inhibition of T cell receptor signaling. Approaches are described to support this hypothesis specifically in view of the necessity for receptors to associate with each other in order to transmit activation signals.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI043954-03
Application #
6373987
Study Section
Immunological Sciences Study Section (IMS)
Program Officer
Quill, Helen R
Project Start
1999-06-01
Project End
2003-05-31
Budget Start
2001-06-01
Budget End
2002-05-31
Support Year
3
Fiscal Year
2001
Total Cost
$180,895
Indirect Cost
Name
University of Southern California
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
041544081
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
Aswad, Fred; Dennert, Gunther (2006) P2X7 receptor expression levels determine lethal effects of a purine based danger signal in T lymphocytes. Cell Immunol 243:58-65
Kawamura, Hiroki; Aswad, Fred; Minagawa, Masahiro et al. (2006) P2X7 receptors regulate NKT cells in autoimmune hepatitis. J Immunol 176:2152-60
Kawamura, Hiroki; Govindarajan, Sugantha; Aswad, Fred et al. (2006) HCV core expression in hepatocytes protects against autoimmune liver injury and promotes liver regeneration in mice. Hepatology 44:936-44
Dennert, Gunther; Aswad, Fred (2006) The role of NKT cells in animal models of autoimmune hepatitis. Crit Rev Immunol 26:453-73
Reszka, Krzysztof J; Britigan, Laura H; Britigan, Bradley E (2005) Oxidation of anthracyclines by peroxidase metabolites of salicylic Acid. J Pharmacol Exp Ther 315:283-90
Aswad, Fred; Kawamura, Hiroki; Dennert, Gunther (2005) High sensitivity of CD4+CD25+ regulatory T cells to extracellular metabolites nicotinamide adenine dinucleotide and ATP: a role for P2X7 receptors. J Immunol 175:3075-83
Minagawa, Masahiro; Kawamura, Hiroki; Liu, Zhangxu et al. (2005) Suppression of adenoviral gene expression in the liver: role of innate vs adaptive immunity and their cell lysis mechanisms. Liver Int 25:622-32
Reszka, Krzysztof J; Wagner, Brett A; Burns, C Patrick et al. (2005) Effects of peroxidase substrates on the Amplex red/peroxidase assay: antioxidant properties of anthracyclines. Anal Biochem 342:327-37
Olakanmi, Oyebode; Stokes, John B; Britigan, Bradley E (2005) Gallium-inducible transferrin-independent iron acquisition is a property of many cell types: possible role of alterations in the plasma membrane. J Investig Med 53:143-53
Kawamura, Hiroki; Aswad, Fred; Minagawa, Masahiro et al. (2005) P2X7 receptor-dependent and -independent T cell death is induced by nicotinamide adenine dinucleotide. J Immunol 174:1971-9

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