Modulation of a PKA-Csk-Lck inhibitory pathway in T cell lipid rafts by CD28-mediated recruitment of a b-arrestin/phosphodiesterase complex

The goal of this project is to understand the molecular mechanisms for cAMP inhibition of lymphocyte proliferation and immune functions. Specifically, we want to understand the molecular interactions and spatio-temporal regulation of the newly mapped PKA- type I-Csk inhibitory pathway regulating Src kinase signalling, which is assembled in lipid rafts where the proximal signalling events in T cell activation take place. We wish to disrupt the PKA type I Csk signalling pathway in lymphoid cells and to study the impact on immunodeficiencies relating to cancer and viral disease. Furthermore, we have discovered a mechanism whereby the T cell following a CD28 stimulus releases cAMP inhibition of proliferation and permits mitogenic stimulation of T cells through recruitment of a PDE/beta arrestin complex. Targets for these strategies are putative therapeutic approaches to treatment of immunodeficiencies. By elimination of PKA type I effects in patient immune cells, the dysfunction can be reversed and this may po tentially be a useful adjuvant therapy.