The role of protein kinase B (PKB/Akt) in T lymphocyte development, function, and survival

T lymphocytes require survival signals to maintain their viability. Understanding the molecular mechanisms that control T cell viability is important since deregulated cell survival has been shown to contribute to the development of several diseases including autoimmunity and cancer. This thesis examines the role of the serine/threonine kinase protein kinase B (PKBα/Akt1) in the regulation of T cell survival in vitro and in vivo. The first study in this thesis employed transgenic mice expressing an active form of PKB (gag-PKB) in the T cell lineage to examine the effect of PKB signaling on the survival of developing thymocytes and mature T cells. The expression of gag-PKB conferred a survival advantage to both mature and immature T cells in response to various apoptotic stimuli, and specifically promoted the survival of thymocytes during developmental processes in the thymus. A second study in the thesis examined the role of PKB in the control of T cell deletion mediated by Fas, a major regulator of T cell apoptosis and general immune homeostasis. It was discovered that the T cell costimulatory molecule CD28 was required to protect CD4+ T cells from apoptosis induced by Fas, and that functional activation of phosphatidylinositol 3 ′-kinase (PI3K) and PKB downstream of CD28 was required to prevent Fas-induced death. Additional experiments established that PKB mediates its anti-apoptotic effects in this model largely through activation of the NF-κB signaling pathway. The final study of the thesis examined the impact of gag-PKB expression upon homeostatic regulation of the immune system. Expression of gag-PKB promoted the development of a lymphoproliferative disorder characterized by the accumulation of activated lymphocytes and the development of systemic inflammatory autoimmune disease. Using gene-targeted mice, it was determined that CD28 is required for the development of this disorder. Collectively these studies establish PKB as a key regulator of T cell apoptosis, define PKB as a central figure in an anti-apoptotic signaling arm downstream of CD28, and identify NF-κB as a mediator of anti-apoptotic PKB activity in T cells. Moreover, these studies establish PKB as a novel initiator of autoimmune disease that promotes lymphoid hyperplasia, inflammation and autoimmunity in vivo.