The IL-2 receptor is involved in many aspects of immune function, including proliferation, lymphoid development, and peripheral tolerance. The receptor complex consists of a high affinity binding chain termed alpha, and beta and gammac subunits that mediate signal transduction. Downstream of this complex lie protein kinases, lipid kinases, adaptor molecules, and transcription factors. The precise relationship between the biochemical pathways and lymphocyte responses is still unclear. This research project proposes to elucidate the pathways by which IL-2 regulates T cell proliferation, using the murine T cell line CTLL2 as a model system. Current studies have shown that the proliferative response is regulated by at least two pathways, one involving the molecule Shc and the other potentially involving the transcription factor STAT5. Both these pathways can contribute somewhat to the expression of several pro-mitotic genes, including c-myc, bcl-x, and cyclin D2. The mechanism by which Shc contributes to the T cell proliferative response will be investigated. In addition, the role of MAP kinase and PI3 kinase pathways that lie downstream of Shc will be examined. Novel components of the Shc pathway may be isolated using the yeast-two hybrid strategy. The role of STAT5 in regulating T cell proliferation will be tested using dominant inhibitory forms of STAT5. Finally, IL-2-regulated transcription factors that modulate expression of cyclin D2 will be identified using a cyclin D2-luciferase construct. These studies should establish connections between IL-2 signaling and the control of cell cycle and will further understanding of the molecular regulation of T cell expansion during normal and pathological processes.
