Abstract
The initiation of antibody-mediated immune responses requires the activation of B lymphocytes by two consecutive signals, i.e. antigen-mediated B cell priming followed by T cell-mediated co-stimulation. The two-signals requirement is critical to maintain humoral immune tolerance because mere ligation of the B cell antigen receptor (BCR) in the absence of T cell help induces deletion or anergy of the primed B cell rather than its differentiation into an immune effector cell. The central question of how B cells integrate negative and positive signal input and how this translates into altered gene expression profiles has puzzled immunologists for decades. This seminar summarizes our recent work on the elucidation of BCR-proximal and BCR-distal signaling events. I will describe the role of liquid-liquid phase separation for the multimerization of the cytosolic BCR signal gate keeper, SLP65 (or BLNK), into signaling-competent BCR effector complexes. A special focus will be on a new proteomic approach, which led to the identification of Transcription Factor EB (TFEB) being a central and hitherto unknown regulator of B cell fate decisions. TFEB integrates the information provided by signal 1 and signal 2 and consequently (re-) programs the transcriptional profile of B cells during the germinal center reaction in lymph node follicles. Hence, TFEB represents the first known transcriptional regulator that can explain the proposed two-signals concept of B cell activation.