Kinetic Modeling Reveals a Common Death Niche for Newly Formed and Mature B Cells

Gitit Shahaf,Ramit Mehr,Michael P Cancro,Wasif N Khan

doi:10.1371/journal.pone.0009497

Abstract

BackgroundB lymphocytes are subject to elimination following strong BCR ligation in the absence of appropriate second signals, and this mechanism mediates substantial cell losses during late differentiation steps in the bone marrow and periphery. Mature B cells may also be eliminated through this mechanism as well as through normal turnover, but the population containing mature cells destined for elimination has not been identified. Herein, we asked whether the transitional 3 (T3) subset, which contains most newly formed cells undergoing anergic death, could also include mature B cells destined for elimination.Methodology/Principal FindingsTo interrogate this hypothesis and its implications, we applied mathematical models to previously generated in vivo labeling data. Our analyses reveal that the death rate of T3 B cells is far higher than the death rates of all other splenic B cell subpopulations. Further, the model, in which the T3 pool includes both newly formed and mature primary B cells destined for apoptotic death, shows that this cell loss may account for nearly all mature B cell turnover.Conclusions/SignificanceThis finding has implications for the mechanism of normal mature B cell turnover.

Highlights

Following immunoglobulin (Ig) gene rearrangement and the expression of a functional B cell receptor (BCR) in the bone marrow (BM), immature (IMM) B cells exit to the periphery as transitional (TR) B cells, where they complete maturation and enter the follicular (FO) or marginal zone (MZ) pools [5,6,7,8]
Recent studies in transgenic systems have suggested that FO cells dying from lack of costimulation reacquire the transitional 3 (T3) phenotype [23], suggesting that this is characteristic of cells undergoing anergic death, and implying that at least some of the T3 pool is derived from mature B cells
The results suggest that the T3 B cell subset is a major staging point for B cells undergoing apoptotic death, since this model can account for most TR B cell losses

Summary

Introduction

Following immunoglobulin (Ig) gene rearrangement and the expression of a functional B cell receptor (BCR) (reviewed in [1,2,3,4]) in the bone marrow (BM), immature (IMM) B cells exit to the periphery as transitional (TR) B cells, where they complete maturation and enter the follicular (FO) or marginal zone (MZ) pools [5,6,7,8]. While the elimination of autoreactive B cells can occur at any differentiative stage after functional BCR expression [9,10,11,12,13,14,15,16], most tolerogenic death is believed to occur at the IMM and TR stages, inasmuch as these are the first expressing a functional BCR, and cells within these subsets seem predisposed to BCR-induced death [11,12,15,17,18] Consistent with this view, in vivo labeling studies have revealed that under steady state conditions, only about half a million of the roughly fifteen million IMM BM B cells produced daily survive to join the mature peripheral pools [19,20]. We asked whether the transitional 3 (T3) subset, which contains most newly formed cells undergoing anergic death, could include mature B cells destined for elimination

Methods

Results

Conclusion