Kinetic modeling reveals a common death niche for newly formed and mature B cells

Abstract

Background: B 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 findings: To 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/significance: This finding has implications for the mechanism of normal mature B cell turnover.

Figure 1. The alternative models of developing B cell populations in the spleen.

The main figure shows the one found as the best model in our previous study . The new hypothesis differs from our previous model only in the direction of flow between T3 and mature B cells, as shown in the inset. Cell subsets and parameters represented in our model are shown (see “Methods” for details).

Figure 2. Cell numbers versus time in a simulation of the spleen population model.

These numbers were obtained by a simulation with the parameters set that gave the best fit to the data. Parameter values are given in Table 2. The steady-state numbers are: T1/2: 1.17×10⁶ cells, T3: 1.43×10⁶ cells, and Mature FO: 2.51×10⁶ cells.

Figure 3. BrdU labeling kinetics.

These kinetics were obtained by a simulation of the spleen population model – with the parameter set that gave the best fit to the data . Parameter values are given in Table 2. Simulation results (dashed lines) are presented along with the experimental results (symbols with error bars).

Figure 4. The number of T3 B cells differentiating from the mature compartment per time step.

Here we plotted the mature B cell differentiation term (δ_m3*B_m) in every time step (6 hours), obtained by a simulation of the new hypothesis. The figure shows the steady state that this number reaches within less than 2 months. Parameter values are given in Table 2.

Figure 5. The model without mature B cell death.

In this model, mature B cells do not have a death rate, that is μ_m = 0. The differentiation from B_m to T₃ occurs a rate of δ_m3 = 0.003, thus the T₃ compartment accounts for all the mature B cell turnover. The other parameter values are given in Table 2.