Cell cycle control of B cell homeostasis and differentiation in the antibody response

In an antibody response, resting B cells reenter the cell cycle and proliferate upon antigen and cytokine stimulation. This is driven by cyclin -dependent kinase 4/6 (Cdk) together with their regulatory D-type cyclins, but the differential roles of the cyclin Ds are unknown. We now show, using cyclin D-deficient mice, that cyclin D2 is required for optimal germinal center (GC) B cell expansion and generation of low affinity plasma cells (PCs) in a T-dependent (TD) immune response. Cyclin D1 protein is undetectable. However, cyclin D3 incompletely compensates for the loss of cyclin D2 because cyclin D2 is required to mediate specific physiologic signals for cell cycle activation, while cyclin D3 cooperates with cyclin D2 for maintaining cell cycle progression. In search of such signals, we discovered that BAFF and IL-4, in synergy but not each alone, drive resting B cells into the cell cycle through a rapid and required cyclin D2 induction.;Once activated, B cells undergo clonal expansion and differentiate to PCs. The Cdk4/6 inhibitor, p18INK4c (p18), is critical for inducing G1 arrest and generating functional, end-stage PCs. However, the specific stage during differentiation where p18 acts remains undefined. We now demonstrate that p18 specifically targets rapidly cycling and apoptotic PC precursors (iPCs), which retain activated B cell characteristics but can differentiate to IgG-secreting PCs. The iPC pool is maintained by p18 for timely differentiation to PCs, and enlarged by Bcl-xL overexpression, or loss of Bim. Loss of Noxa, which is preferentially expressed in cycling iPCs and repressed by p18, results in iPC accumulation due to a significant reduction in apoptosis. Furthermore, p18 appears dispensable for the development of the PC transcriptional program but individual PCs express Blimp-1 or Bcl-6, except for a minority expressing both, which are expanded by p18 and protected by Bcl-xL.;Together, these studies demonstrate specific mechanisms whereby the cell cycle controls initiation and termination of a physiologic response. For initiation, D-type cyclins are differentially required due to the specificity with which they are regulated by physiologic signals. For termination, Noxa couples G 1 cell cycle regulation by p18 in iPCs for homeostatic control of PC differentiation.