Abstract
Cellular homeostasis in the B cell compartment is strictly imposed to balance cell production and cell loss. However, it is not clear whether B cell development in the bone marrow is an autonomous process or subjected to regulation by the peripheral B cell compartment. To specifically address this question, we used mice transgenic for human CD20, where effective depletion of B lineage cells is obtained upon administration of mouse anti-human CD20 antibodies, in the absence of any effect on other cell lineages and/or tissues. We followed the kinetics of B cell return to equilibrium by BrdU labeling and flow cytometry and analyzed the resulting data by mathematical modeling. Labeling was much faster in depleted mice. Compared to control mice, B cell-depleted mice exhibited a higher proliferation rate in the pro-/pre-B compartment, and higher cell death and lower differentiation in the immature B cell compartment. We validated the first result by analysis of the expression of Ki67, the nuclear protein expressed in proliferating cells, and the second using Annexin V staining. Collectively, our results suggest that B lymphopoiesis is subjected to homeostatic feedback mechanisms imposed by mature B cells in the peripheral compartment.
Highlights
B cell development starts in the bone marrow (BM) and continues in the spleen to final maturation
To determine whether B lymphopoiesis in the BM is regulated by the size of the peripheral B cell compartment, we used hCD20Tg mice where human CD20 (hCD20) is expressed exclusively on B lineage cells, and administration of anti-hCD20 antibodies has been shown to deplete the peripheral B cells, leaving all other cell lineages intact [25]
Administration of anti-hCD20 antibodies leads in the BM to the rapid elimination of the hCD20+ subgroup of immature B cells as well as circulated mature B cells but leaves the pro-/pre-B cell compartment unchanged (Figure 2B)
Summary
B cell development starts in the bone marrow (BM) and continues in the spleen to final maturation. Further developmental progression and maturation in the periphery are limited by positive and negative selection, mediated by BCR signaling and aiming to construct a nonself-reactive, immune-competent repertoire of naïve B cells [2, 6]. It has been estimated that 1–2 × 107 immature B cells are generated daily in the adult mouse and leave the BM as transitional B cells [7], but only about 3% enter the pool of mature B cells [8]. Another source of B cell input to the peripheral compartment is antigen-driven proliferation. The balance between cell production and cell death maintains the size of the peripheral B cell compartment unchanged [13]
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