The quantity of CD40 signaling determines the differentiation of B cells into functionally distinct memory cell subsets

In mice, memory B (B(mem)) cells can be divided into two subpopulations: CD80(hi) B(mem) cells, which preferentially differentiate into plasma cells; and CD80(lo) B(mem) cells, which become germinal center (GC) B cells during a recall response. We demonstrate that these distinct responses can be B-cell-intrinsic and essentially independent of B-cell receptor (BCR) isotypes. Furthermore, we find that the development of CD80(hi) B(mem) cells in the primary immune response requires follicular helper T cells, a relatively strong CD40 signal and a high-affinity BCR on B cells, whereas the development of CD80(lo) B(mem) cells does not. Quantitative differences in CD40 stimulation were enough to recapitulate the distinct B cell fate decisions in an in vitro culture system. The quantity of CD40 signaling appears to be translated into NF-κB activation, followed by BATF upregulation that promotes B(mem) cell differentiation from GC B cells.