Early, adjuvant-responsive epigenetic programs in B cells imprint subsequent plasma cell survival and the duration of humoral immunity.

The duration of antibody production varies across different infections and vaccines. To define molecular programs that promote durable humoral immunity, we used mice deficient in ZBTB20, a transcription factor that is highly expressed by plasma cells and required to maintain antibody production in vivo. However, genetic deletion of Zbtb20 in long-lived plasma cells had no impact on the duration of antibody production. Instead, deletion of Zbtb20 in B cells only within the first week after immunization caused a subsequent failure to maintain plasma cells. Through single-cell ATAC-sequencing, we observed elevated IRF8- and Ets-dependent epigenetic programs in ZBTB20-deficient B cells at 7 days post-immunization. The corresponding transcriptional changes were observed ~1 week later. Switching from alum to an oil-in-water adjuvant suppressed Ets-dependent epigenetic programs and rescued ZBTB20-deficient antibody responses. Deletion of Irf8 also rescued ZBTB20-deficient antibody responses. Thus, B cell-intrinsic epigenetic programs imprint durable antibody production at an early stage, prior to major transcriptional consequences and weeks before most long-lived plasma cells are formed.