The TACI Receptor Regulates T-Cell-Independent Marginal Zone B Cell Responses through Innate Activation-Induced Cell Death

• TLR4 stimulation upregulates TACI, FasL, and Fas on MZ B cells in vivo
• MZ B cells require TACI for optimal LPS-driven FasL and Fas upregulation and apoptosis
• TACI represses expression of Fas-mediated apoptosis inhibitors in B cells
• FasL-dependent but T-cell-independent innate AICD regulates B cell activation

SummaryActivation-induced cell death (AICD) plays a critical role in immune homeostasis and tolerance. In T-cell-dependent humoral responses, AICD of B cells is initiated by Fas ligand (FasL) on T cells, stimulating the Fas receptor on B cells. In contrast, T-cell-independent B cell responses involve innate-type B lymphocytes, such as marginal zone (MZ) B cells, and little is known about the mechanisms that control AICD during innate B cell responses to Toll-like receptor (TLR) activation. Here, we show that MZ B cells undergo AICD in response to TLR4 activation in vivo. The transmembrane activator, calcium modulator, and cyclophilin ligand interactor (TACI) receptor and TLR4 cooperate to upregulate expression of both FasL and Fas on MZ B cells and also to repress inhibitors of Fas-induced apoptosis signaling. These findings demonstrate an unappreciated role for TACI and its ligands in the regulation of AICD during T-cell-independent B cell responses.