| Cytokines act by binding to receptors on their target cell surfaces, and these receptors subsequently mediate the delivery of highly specific molecular signals that determine the response of the target cell. In the absence of proper cytokine function, which may occur by a genetic defect in the cytokine, its receptor, or a downstream signaling molecule, severe immune deregulation can result. The most common form of congenital immunodeficiency (X-linked severe combined immunodeficiency, X-SCID) is due to an inherited defect in a cytokine receptor gene, known as the common gamma chain (gammac). This research described helps define the molecular basis for signaling by gammac, using the interleukin (IL)-2 receptor system as a model, with the ultimate goal of developing improved therapeutic strategies for treating immune deficiency or other diseases involving IL-2. Accordingly, the studies in this dissertation are aimed at defining the molecular mechanisms by which IL-2 promotes T cell survival, which is essential for proper development and maintenance of the immune system. Considerable research has demonstrated that a critical function of cytokine receptors is to promote cellular survival by delivering signals that protect lymphocytes from apoptosis. One such survival signal particularly important in T cells is the upregulation of the anti-apoptotic protein Bcl-2. Indeed, many of the genetic defects observed in mice with a targeted deletion in the gammac gene (a model for X-SCID) can be rescued by ectopic expression of Bcl-2. Specifically, we have discovered a novel anti-apoptotic pathway that is mediated by tyrosine residues of the gammac subunit. This pathway is sensitive to the PI 3K family inhibitors wortmannin and LY294002. Interestingly, this gammac-dependent pathway does not activate the "classic" PI 3K regulatory subunits p85alpha/beta. However, studies using pharmacological inhibitors and biochemical analyses indicates the roles for AKT and the PI 3K family members p110delta and p55PIK. |
