New insights to B cell tolerance involving the mechanosensitive ion channel Piezo1.

B cell tolerance is critical for preventing autoimmunity, yet the mechanisms by which B cells discriminate self from non-self antigens remain incompletely understood. While early findings emphasize the role of classical antigen-mediated BCR signaling strength by varying antigen formats, emerging evidence highlights the importance of mechanical cues during antigen recognition. This review explores how mechanosensitive ion channels, particularly Piezo1, contribute to B cell activation and tolerance by integrating physical forces at the immune synapse. We discuss how membrane-bound and particulate antigens induce mechanotransduction through Piezo1, promoting enhanced B cell responses by extracellular calcium influx. Additionally, we consider the differential roles of Piezo1 in various physiological contexts, including shear stress, tissue migration, and substrate stiffness. Understanding mechanosensor-mediated signaling in coordination with other pathways such as antigen recognition, T cell help, or cytokine signaling expands our knowledge of B cell biology and introduces a new paradigm for modulating humoral immunity in health and disease.