A01: Apoptosis and survival in response to TRAIL signaling in human B cell homeostasis

Project Leader: Marta Rizzi

The homeostasis of the human B cell compartment requires a precise balance between pro-survival signals and apoptotic signals in the different maturation stages. Furthermore, during activation B cell integrate signals deriving from the environment to define their fate. TRAIL receptors (TRAIL-R) are known to induce apoptosis in cancer cells (TRAIL-R1 and 2) or modulate ligand availability (TRAIL-R3 and 4). We demonstrated that TRAIL-R1-4 expression changes during B cell maturation, and is dynamically regulated upon activation in a B cell subpopulation-specific manner. In line with these data, primary human B cells ex vivo, or shortly (1 day) after activation do not undergo apoptosis upon TRAIL-R activation, and sensitivity to apoptosis is only acquired after 2-3 days of activation. We hypothesize that TRAIL-Rs contribute with either survival or apoptotic signals to B cell homeostasis in humans. Hence, we aim to determine the frame and the conditions at which B cell cells survive or undergo apoptosis in response to TRAIL, by testing different B cell subpopulation, time and type of stimulations, as well as the specific roles of TRAIL-R1 and TRAIL-R2 in this process. Based on that we aim at determining the molecular mechanisms underlying the decision between life and death upon TRAIL-R activation, focusing on the membrane localisation of TRAIL-Rs and the composition of the death-inducing signaling complex (DISC) in the different situations. Finally, we will focus on the role of caspase 8, which is a key mediator of TRAIL-R signaling and can convey for apoptotic and survival signals in different contexts. Our work will reveal the physiological role of TRAIL-Rs in human primary B cells homeostasis, with relevant translational aspects to TRAIL-R-targeting therapies.