Distinction of the memory B cell response to cognate antigen versus bystander inflammatory signals

The hypothesis that bystander inflammatory signals promote memory B cell (B-MEM) self-renewal and differentiation in an antigen-independent manner is critically evaluated herein. To comprehensively address this hypothesis, a detailed analysis is presented examining the response profiles of B-2 lineage B220(+)IgG(+) B-MEM toward cognate protein antigen in comparison to bystander inflammatory signals. After in vivo antigen encounter, quiescent B-MEM clonally expand. Surprisingly, proliferating B-MEM do not acquire germinal center (GC) B cell markers before generating daughter B-MEM and differentiating into plasma cells or form structurally identifiable GCs. In striking contrast to cognate antigen, inflammatory stimuli, including Toll-like receptor agonists or bystander T cell activation, fail to induce even low levels of B-MEM proliferation or differentiation in vivo. Under the extreme conditions of adjuvanted protein vaccination or acute viral infection, no detectable bystander proliferation or differentiation of B-MEM occurred. The absence of a B-MEM response to nonspecific inflammatory signals clearly shows that B-MEM proliferation and differentiation is a process tightly controlled by the availability of cognate antigen.