NOVEL T CELL ACTIVATION GENE IN DEVELOPING NEURONS

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DESCRIPTION (Adapted from applicant's abstract): Mental effects on physical health are mediated by interactions between the nervous and immune systems. These systems are coordinately regulated through common molecules. Given the common expression of cell surface receptors and soluble mediators in both systems, one might expect to find intracellular proteins that are common to both systems and may be involved in signaling. The investigators isolated a cDNA sequence from a cDNA library prepared from IL2-stimulated, cloned T lymphocytes which has recently been identified as the KvBeta2 subunit of voltage-gated K channels. Potassium channels maintain membrane potential and determine the excitability of cells. Beta subunits appear to regulate the conductance properties of K channels. KvBeta2 is expressed in proliferating lymphocytes and postnatal neurons. The hypothesis proposed is that Beta subunit expression affects lymphocyte and neuronal function through modulation of K channel conductance. The first aim will test the hypothesis that Beta subunit expression is required for IL2-driven T cell proliferation. The investigators indicate that with their knowledge of IL-2 induced gene expression, the precise point at which cell cycle progression is inhibited will be determined. In a second aim, studies will be initiated to define cis elements in a Beta subunit promoter and corresponding DNA binding proteins which are responsible for IL2-induced Beta subunit expression in lymphocytes. In a third aim, activation-dependent phosphorylation sites on Beta subunits will be determined in vitro and in vivo. Once specific phosphoamino acids are found, mutant proteins precluding specific phosphorylation will be prepared to determine the requirement of phosphorylation for Beta subunit function during IL2-driven proliferation. To determine if Beta subunit is required for lymphocytic and neuronal development and function, mice homozygous for a Beta subunit null allele will be prepared. While these animals may be immunodeficient at birth, the effect of Beta subunit deletion on neuronal development should not appear until postnatal neuronal maturation occurs. These studies will define the functional significance for KvBeta subunits in both the nervous and immune systems and begin to address molecular mechanisms regulating tissue specific expression.