Heme enhances B-cell proliferation and plasma cell formation through reduced p21 and Rb expression.

Antibodies are secreted by specialized antibody-secreting cells, also known as plasma cells (PCs), which differentiate from antigen-activated B cells. Antibodies are critical for protection against many types of infection and are correlates of vaccine efficacy. Iron metabolism is important for antibody responses, and heme (the major source of Fe2+) augments PC formation. However, the full spectrum of heme-molecular interactions and effects during B-cell differentiation are not fully understood. Here, we found that heme treatment of differentiating mouse B cells resulted in significant augmentation of the gene expression and chromatin accessibility landscape of both activated B cells and PC, with the largest effect occurring in genes regulating the G1 to S cell cycle transition. Consistent with this effect, naïve and memory B cells displayed enhanced proliferation and PC formation in the presence of heme. BrdU incorporation analysis revealed this was due to more DNA replication in later cell divisions, indicating more cells transitioning from G1 to S phase of the cell cycle. This occurred through diminished levels of p21 and Rb, which are key negative regulators of the G1/S cell cycle checkpoint. Altogether, this study shows that heme contributes to PC differentiation by regulating the G1 to S cell cycle phase transition through modulation of the p21-Rb regulatory axis.