During the course of an immune response, T cells are confronted with a number of stages where appropriate decisions between survival, proliferation and death are crucial. Although many of these choices are regulated by distinct signal transduction pathways, it is becoming clear that some of the molecules regulating these disparate pathways are shared in common. We have discovered a novel pathway involving FADD/Mortl, that links apoptotic control in T cells to cellular growth control. FADD is a cytoplasmic adapter molecule that physically associates with death receptors and caspase-8 and -10; this association results in caspase activation. Using mice expressing a mutant form of FADD in T cells, we have demonstrated that this apoptosis-inducing molecule is critical for normal T cell responsiveness to a number of mitogenic stimuli. We outline several approaches in this proposal to more fully understand the means by which FADD coordinates the choice between proliferation and apoptosis in T cells. In this proposal, we will first determine if FADD is required for the proliferation of T cells that have differentiated in a normal background. This will allow us to distinguish the role of FADD in the development of T cells from its potential to act as a costimulatory signaling component in mature peripheral T cells. Next, we will study the activation of known signaling pathways in the context of T cells expressing dominant negative FADD to determine how FADD participates in the institution and maintenance of proliferating CD4+ and CD8+ T cells. We will also address the potential that caspase-8 may play a role in this FADD-dependent costimulatory process by introducing dominant-negative forms of caspase-8 into primary T cells. Further, we will study the differential processing of caspase-8 to understand how this molecule might induce and maintain proliferation in a T cell response and later, potentiate activation-induced cell death. The mechanism by which FADD regulates both proliferation and apoptosis in T cells is an enigma. However, it is clear that both proliferative and apoptotic regulation of this compartment of the immune system is crucial for the avoidance of cancers, autoimmunity and pathogenesis. Therefore, results from these proposed studies will not only shed light on an important molecule linking these two processes, but will also highlight a signaling paradigm that is critical for the evasion of human disease. ? ?
