Conventional and Alternative B Lymphopoiesis: Multiple Roads to Immunity

Hematopoiesis is a dynamic, adaptive process that governs blood and immune cell production through coordinated self-renewal, proliferation and differentiation. Shaped by intrinsic cell heterogeneity, environmental cues and physiological demands, it ensures effective blood cell production under both steady-state and stress conditions. Advances in single-cell and lineage-tracing technologies have shifted the traditional hierarchical view of hematopoiesis toward a flexible, interconnected network. B cell development exemplifies this plasticity, involving coordinated genetic and environmental signals to generate diverse subsets. Beyond the classical common lymphoid progenitors (CLP)-dependent model, B cells can also arise through alternative pathways, including direct differentiation from HSCs or at extramedullary sites like the spleen. Environmental signals and niche-specific factors support this diversity. Bipotent progenitors linking B lymphoid and myeloid (macrophage/osteoclast) fates have been identified in both fetal and adult hematopoiesis, revealing overlapping lineage potential and developmental flexibility. Moreover, mature B cells exhibit functional adaptability. B2 cells can convert into B1 cells under certain conditions, while CD11b⁺ myeloid-like B cells (M-B cells) emerge during emergency myelopoiesis, highlighting functional plasticity beyond antibody production. This evolving understanding redefines B cells as versatile immunoregulatory players, especially during inflammation and immune stress and opens new avenues for therapeutic interventions in immunity and hematologic disorders.