Programming plasma cell survival

744 INSIGHTS | The Journal of Experimental Medicine In this issue, two independent groups show that the transcription factor ZBTB20 is required for the maintenance of long-lived plasma cells following immunization with the commonly used adjuvant, alum. Intriguingly, one group found that ZBTB20 was dispensable for plasma cell survival when they used adjuvants that activate Toll-like receptors (TLRs). Protection from recurrent infections depends on long-lived plasma cells secreting high-affinity antibodies, which are generated during T cell–dependent immune responses in the germinal center reaction. But not all vaccinations or infections yield durable and protective plasma cell responses. Therefore, a better understanding of the molecular mechanisms that govern plasma cell generation and maintenance is needed in order to develop more effective vaccines. Chevrier et al. and Wang and Bhattacharya now show that the BTB-POZ transcription factor ZBTB20, which is expressed in germinal center B cells and at high levels in plasma cells, is crucial for maintaining durable antibody responses by promoting cell survival following immunization of mice with a model antigen in alum. But when Wang and Bhattacharya administered the same antigen with TLR-ligand based adjuvants they observed that ZBTB20 was dispensable for the development and survival of plasma cells. Both ZBTB20-dependent and -independent plasma cell survival pathways were B cell–intrinsic, suggesting that the immune cells activated by the corresponding adjuvants imprint longevity on the plasma cells when they are formed within the germinal centers. The mechanisms underlying this imprinting process are presently unknown and require further investigation. Chevrier et al. show clearly that the control of ZBTB20 expression differs fundamentally between germinal center B cells and plasma cells. Zbtb20 is a transcriptional target of the plasma cell master regulator IRF4 in plasma cells, but not in the majority of germinal center B cells, which lack IRF4. However, IRF4 expression is up-regulated in a small subset of late germinal center B cells that are plasma cell precursors. It is therefore possible that the ZBTB20-dependent survival program is initiated at this developmental stage through interaction with T follicular helper cells. Similarly, this particular germinal center subpopulation may be the downstream target of TLR-ligand based adjuvants. It will be important to identify the ZBTB20-equivalent transcription factor, which Wang and Bhattacharya suggest might be another BTB-POZ transcription factor, ZBTB32. An important implication of the current studies is that we need to dissect the transcription factor network that controls plasma cell generation within the germinal center in order to understand how adjuvants improve the durability of vaccines. In addition, the results clearly indicate that in vaccine development, it is important to know whether an infection triggers an alum-like or TLR-biased response. The findings also serve as a reminder to be more cautious with generalizing results obtained from the study of a single immunization model.