Abstract
The maintenance of B cell homeostasis requires a tight control of B cell generation, survival, activation, and maturation. In lymphocytes upon activation, increased sensitivity to apoptotic signals helps controlling differentiation and proliferation. The death receptor Fas is important in this context because genetic Fas mutations in humans lead to an autoimmune lymphoproliferative syndrome that is similar to lymphoproliferation observed in Fas-deficient mice. In contrast, the physiological role of TNF-related apoptosis-inducing ligand receptors (TRAIL-Rs) in humans has been poorly studied so far. Indeed, most studies have focused on tumor cell lines and on mouse models whose results are difficult to transpose to primary human B cells. In the present work, the expression of apoptosis-inducing TRAIL-R1 and TRAIL-R2 and of the decoy receptors TRAIL-R3 and TRAIL-R4 was systematically studied in all developmental stages of peripheral B cells isolated from the blood and secondary lymphoid organs. Expression of TRAIL-Rs is modulated along development, with highest levels observed in germinal center B cells. In addition, T-dependent and T-independent signals elicited induction of TRAIL-Rs with distinct kinetics, which differed among B cell subpopulations: switched memory cells rapidly upregulated TRAIL-R1 and -2 upon activation while naïve B cells only reached similar expression levels at later time points in culture. Increased expression of TRAIL-R1 and -2 coincided with a caspase-3-dependent sensitivity to TRAIL-induced apoptosis in activated B cells but not in freshly isolated resting B cells. Finally, both TRAIL-R1 and TRAIL-R2 could signal actively and both contributed to TRAIL-induced apoptosis. In conclusion, this study provides a systematic analysis of the expression of TRAIL-Rs in human primary B cells and of their capacity to signal and induce apoptosis. This dataset forms a basis to further study and understand the dysregulation of TRAIL-Rs and TRAIL expression observed in autoimmune diseases. Additionally, it will be important to foresee potential bystander immunomodulation when TRAIL-R agonists are used in cancer treatment.
Highlights
The homeostasis of humoral immunity requires a tight control of generation, survival, activation and maturation of B lymphocytes
We studied the sensitivity to apoptosis in response to TRAIL, the activation of effector caspases and the respective contribution of TRAIL-R1 and TRAIL-R2 to the apoptosis induction in primary human B cells
We found that the expression of TRAIL-Rs is modulated along development, with germinal center (GC) B cells expressing highest levels of all TRAIL receptors compared to all other B cell subpopulations
Summary
The homeostasis of humoral immunity requires a tight control of generation, survival, activation and maturation of B lymphocytes. Pro-survival and pro-apoptotic signals play a very important role in shaping the B cell repertoire and the long-term memory compartment. Activation-induced cell death (AICD) is a key mechanism in the control of cell expansion and selection in the germinal center (GC), where B cells are activated and change their affinity for the antigen via somatic hypermutation [1]. Several members of the tumor necrosis factor (TNF) receptor superfamily have been implicated in the control of B cell homeostasis. Fas (CD95, Apo-1) is involved in the control of B cell activation and GC selection [4]. Mutations in Fas lead to lymphoproliferation of B and T cells, and to autoimmunity [5, 6]
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