Activated T cell death: molecular mechanisms and implications of T cell function

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During an adaptive immune response, antigen-specific T cells expand massively. When the infectious agent has been cleared away, the vast majority of activated T cells die by apoptosis, and this cell death is believed to be important to prevent autoimmunity and immunopathology and to regulate immunologic memory. Although it is clear that activated T cell death is regulated mainly by proteins of the Bcl-2 family, especially Bim, the molecular events governing this regulation remain elusive. We have identified a number of candidate molecules and signalling events that may orchestrate the activation of Bim and its relative Puma in activated T cell death. Molecular modifications of Bim/Puma, cytokine signalling through Stat5 as well as NF-κB family members, possibly acting through the regulation of chemokine receptors, all appear to play roles in the transcriptional and post-translational activation of Bim. The main goal of this project is the molecular delineation of these signalling pathways in order to understand the upstream events in this important step in the regulation of immune homeostasis. Using genetically modified mice we will further address the question of the relative importance of T cell vs. APC apoptosis in the maintenance of functional CD8+ T cells. We expect that the results from these experiments will clarify important aspects of activated T cell death and permit new approaches to its therapeutic and preventative manipulation.