Posdoctoral Research Scientist Columbia University New York, New York, United States
Introduction/Rationale: Effective clearance of systemic infections requires rapid antibody production mediated in part by marginal zone (MZ) B cells. MZ B cells also augment high-affinity antibody responses generated by follicular (FO) B cells, and their dysregulation is linked to sepsis, infections by encapsulated bacteria, and autoimmunity. Despite their importance, the quantitative mechanisms governing MZ B cell development, longevity, and population structure remain unclear. Although traditionally viewed as long-lived and self-renewing, recent studies suggest MZ B cells arise from a heterogeneous pool of transitional and potentially FO, B cells.
Methods: We addressed these questions by integrating mathematical modeling with in vivo experiments. Using a bone marrow chimera model, we quantified precursor influx into the MZ B cell compartment under steady-state conditions and assessed whether replenishment persists throughout life. This approach also provides quantitative measurements of proliferation, turnover, and constitutive replenishment rates. Early-life data further illuminate the effects of population density on MZ B cell establishment and kinetics.
Results: Our analyses reveal that MZ B cells are a short-lived, homogeneous population maintained by continuous influx from both early- and late-stage transitional B cells. In early life, MZ B cell accumulation is inefficient, and cells divide more frequently under low-density conditions, consistent with an incompletely occupied niche. As the compartment fills in adulthood, competition for limiting homeostatic resources restricts MZ B cell self-renewal, such that steady-state maintenance of the adult MZ B cell pool is dominated by ongoing precursor-derived influx.
Conclusion: These findings revise the prevailing model of MZ B cell homeostasis, revealing continuous replenishment rather than self-renewal as the dominant maintenance mechanism. Together, our results provide a unified, age-dependent view of MZ B-cell development from neonatal life to adulthood.
