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.
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