Project B17 – The role of the CARD8 inflammasome in controlling T cell fate
Conducting a systematic perturbation of inflammasome components in human primary T cells, we have made the surprising observation that T cells are indeed highly responsive to the activation of the CARD8 inflammasome but not other inflammasome pathways. CARD8 activation results in the robust activation of caspase-1 and induces a gasdermin D (GSDMD)-dependent pyroptotic cell death, which is inhibited by TCR engagement. In the upcoming funding period we want to understand how CARD8-triggered cell death is used in relation to other, already well-defined cell death pathways and how the activation status (TCR signaling) impacts in this cascade. In addition, we want to characterize the physiological role of pyroptosis in T cells and also explore inflammasome functionalities beyond cell death. To achieve these goals, we will study in vitro engineered primary lymphocytes as well as humanized mice, in which the fate of CARD8-deficient lymphocytes can be mapped in the context of different immune activation states in vivo.