Signaling Activation and Modulation in Extrafollicular B Cell Responses

ABSTRACT The differentiation of naive follicular B cells into either the germinal center (GC) or extrafollicular (EF) pathway plays a critical role in shaping the type, affinity, and longevity of effector B cells. This choice also governs the selection and survival of autoreactive B cells, influencing their potential to enter the memory compartment. During the first 2–3 days following antigen encounter, initially activated B cells integrate activating signals from T cells, Toll‐like receptors (TLRs), and cytokines, alongside inhibitory signals mediated by inhibitory receptors. This integration modulates the intensity of signaling, particularly of the PI3K/AKT/mTOR pathway, which plays a central role in guiding developmental decisions. These early signaling events determine whether B cells undergo GC maturation or differentiate rapidly into antibody‐secreting cells (ASCs) via the EF pathway. Dysregulation of these signaling pathways—whether through excessive activation or defective regulatory mechanisms—can disrupt the balance between GC and EF fates, predisposing individuals to autoimmunity. Accordingly, aberrant PI3K/AKT/mTOR signaling has been implicated in the defective selection of autoreactive B cells, increasing the risk of autoimmune disease. This review focuses on the signaling events in newly activated B cells, with an emphasis on the induction and regulation of the PI3K/AKT/mTOR pathway. It also highlights gaps in our understanding of how alternative B cell fates are regulated. Both the physiological context and the implications of inborn errors of immunity (IEIs) and complex autoimmune conditions will be discussed in this regard.