The interplay between PLC gamma 2 and PI3K pathways determines the fate of an activated B cell 4183

Abstract Description Antigen binding to B cell receptor (BCR) (signal one) initiates a ‘metabolic clock’ during which the cell can receive a ‘signal two’ for survival, either from T helper cells or Toll-like receptors. Without the second signal, the B cell faces elimination due to mitochondrial dysfunction. BCR-induced mitochondrial dysfunction is caused by calcium increase, resulting in mitochondrial swelling. However, the mechanisms by which BCR increases calcium and how this can be prevented by signal two have remained unclear. Here, using signaling modulators on primary human and mouse B cells as well as on transgenic mice, we reveal that BCR-induced calcium imbalance is caused by the prolonged activity of the PLC gamma2-IP3 pathway, facilitating the passive influx of calcium into the cytoplasm and second signals counteract this effect by instigating PI3k-Akt pathway-dependent ATP production, thereby supporting active calcium exporters. Additionally, we have discovered that mitochondrial remodeling, encompassing mitophagy, biogenesis, and modulation of mitochondrial pore complex activity, serves as intricate regulators, defining the calcium concentration threshold capable of inducing mitochondrial dysfunction. Ultimately, the relative strengths of these processes determine not only cell death or cell survival but also the induction of cellular anergy. Altogether, our work has unveiled the mechanism behind the metabolic clock, the cornerstone of the B cell fate decision process. Funding Sources NIH/ NIGMS R35 GM155038 Topic Categories Lymphocyte Differentiation and Peripheral Maintenance (LYM)