Transcription factor EB sets the stage for B cell fate decisions and humoral responses to foreign and self

The B cell antigen receptor (BCR) constitutes the defining hallmark of B lymphocytes, governing their development, activation, and effector differentiation. In the context of humoral immunity, however, mere BCR ligation without appropriate co-stimulation triggers functional silencing or ‘death-by-default’ as a failsafe against self-reactivity while ensuring effective immune responses to pathogens. Yet, the transcriptional logic that balances activation with deletion and determines B cell effector outcomes, remains poorly understood. Classical lineage- and subtype-defining transcription factors alone fail to explain how BCR signaling translates into such divergent cellular fates. Previously, in an unbiased proteomic screen designed to catalogue signal-response nuclear shuttling proteins, our laboratory identified the hitherto uncharacterized transcription factor EB (TFEB) as a robustly antigen-inducible element in B lymphocytes. TFEB translocated to the nucleus with unprecedented speed and magnitude, surpassing established transcriptional regulators and positioning it as a novel mediator linking BCR antigen recognition to transcriptional output. While TFEB is classically recognized as a master regulator of lysosomal biogenesis and autophagy, its immunological contribution to B-lymphoid activation and humoral responses had not been explored. Here, by combining cross-species TFEB-deficient B cell lines with conditional deletion of TFEB in the murine B cell lineage, I established TFEB’s dual responsiveness to antigenic and metabolic cues, demonstrating its essential role in B cell activation and effector function. In vivo, TFEB loss caused a developmental bottleneck with reduced B cell numbers and smaller spleens. Despite impaired germinal center (GC) formation, TFEB-deficient mice generated exaggerated antigen-specific effector B cell populations, reflecting defective apoptotic culling within the GC. TFEB deletion further skewed post- GC differentiation toward memory B cells at the expense of plasma cells, which in turn exhibited a hypersecretory phenotype. Reduced GC selection stringency promoted self-reactive B cell formation and elevated autoantibody titers, accompanied by a cytokine milieu biased toward pro-inflammatory profiles. Collectively, this work identifies TFEB as a BCR-mediated rheostat that integrates antigenic and co-stimulatory cues into a transcriptional program balancing the dual outcomes of BCR signaling. By simultaneously promoting activation-induced cell death and equipping primed B cells to receive T cell help through enhanced chemokine-guided migration and fostered antigen presentation, TFEB sets the stage for B-lymphoid fate decisions. Thus, TFEB orchestrates subset composition and effector function, while safeguarding productive yet self-tolerant humoral immunity to foreign antigens.