Maturation of Human Long-lived Plasma Cells Results in Resistance to Apoptosis by Transcriptional and Epigenetic Regulation

Antibody secreting cells (ASC) circulate after vaccination and migrate to the bone marrow (BM) where a subset known as long-lived plasma cells (LLPC) persist and secrete antibodies for a lifetime. The mechanisms of how circulating ASC become LLPC are not well elucidated. Here, we show that human blood ASCs have distinct morphology, transcriptomes, and epigenetics compared to BM LLPC. LLPC acquire transcriptional and epigenetic changes in the apoptosis pathway to support their survival. Upregulation of pro-survival gene expression accompanies downregulation of pro-apoptotic gene expression in LLPC. While pro-apoptotic gene loci are less accessible, pro-survival gene loci are not always accompanied by accessibility changes. Importantly, we show similar LLPC morphological and transcriptional maturation of blood ASC in response to the novel in vitro BM mimetic. In all, our study demonstrates that blood ASC in the BM microniche must undergo morphological and molecular changes to mature into apoptotic-resistant LLPC. ### Competing Interest Statement FEL is the founder of Micro-Bplex, Inc. FEL serves on the scientific board of Be Bio Pharma, is a recipient of grants from the BMGF and Genentech, Inc. FEL has also served as a consultant for Astra Zeneca. Emory has applied to patents concerning the plasma cell survival media related to this work: FEL, DN, and IS are inventors. All other authors have declared no conflicts of interest.