Distinct T helper cell dependence of memory B‐cell proliferation versus plasma cell differentiation

Several memory B‐cell subclasses with distinct functions have been described, of which the most effective is the class‐switched (CS) memory B‐cell population. We have previously shown, using virus‐like particles (VLPs), that the proliferative potential of these CS memory B cells is limited and they fail to re‐enter germinal centres (GCs). However, VLP‐specific memory B cells quickly differentiated into secondary plasma cells (PCs) with the virtue of elevated antibody production compared with primary PCs. Whereas the induction of VLP+ memory B cells was strongly dependent on T helper cells, we were wondering whether re‐stimulation of VLP+ memory B cells and their differentiation into secondary PCs would also require T helper cells. Global absence of T helper cells led to strongly impaired memory B cell proliferation and PC differentiation. In contrast, lack of interleukin‐21 receptor‐dependent follicular T helper cells or CD40 ligand signalling strongly affected proliferation of memory B cells, but differentiation into mature secondary PCs exhibiting increased antibody production was essentially normal. This contrasts with primary B‐cell responses, where a strong dependence on CD40 ligand but limited importance of interleukin‐21 receptor was seen. Hence, T helper cell dependence differs between primary and secondary B‐cell responses as well as between memory B‐cell proliferation and PC differentiation.