REGULATION OF IMMUNE RESPONSE AND CELL GROWTH

University Of California Davis, Davis CA

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Abstract

The long term goal is an understanding of the immune response and immune system cell growth regulation. The battle against infectious microorganisms involves cascades of events in innate and acquired immunity, and remarkable conservation has been observed from flies to mammals in Toll and NFkB signalling pathways. Using Drosophila, we have identified a new gene, Thor, in the cascade of events in response to bacterial infection. Thor encodes the Drosophila counterpart of mammalian 4E-binding proteins (4E-BP), which act to inhibit 5' cap-dependent translation by binding to eukaryotic initiation factor 4E (elF-4E). The upstream region of Thor has kB sequences and other motifs characteristic of immune induction, and upon bacterial infection the level of Thor transcripts is increased. Thor has thus opened a new avenue of investigation by revealing that a repressor of translation is induced in the host response to bacterial infection. In addition, in mammalian cells eIF4E overexpression has been found to be oncogenic, and this transformation can be blocked by overexpressing 4E-BP. Our identification of Thor and its immune induction thus provides the first opportunity to 1) couple the well established transcriptional regulation and signal transduction pathways in immune induction with a translational component, 2) analyze the role of translation in effecting the immune response, and 3) study immune system cell growth regulation via translational control. These studies also have the advantage and opportunity of genetic manipulation and analysis in vivo. Study of this newly discovered host immune response can thus help us to understand fundamental immune mechanisms and growth regulation, which will contribute toward definition and treatment of immune disorders, difficult to treat infections, and cancer.