Abstract
Antibody secreting cells (ASCs) circulate after vaccination and infection and migrate to the BM where a subset known as long-lived plasma cells (LLPCs) persists and secrete antibodies for a lifetime. The mechanisms by which circulating ASCs become LLPCs are not well elucidated. Here, we show that human blood ASCs have distinct morphology, transcriptomes, and epigenetics compared with BM LLPCs. Compared with blood ASCs, BM LLPCs have decreased nucleus/cytoplasm ratio but increased endoplasmic reticulum and numbers of mitochondria. LLPCs up-regulate pro-survival genes MCL1, BCL2, and BCL-XL while simultaneously down-regulating pro-apoptotic genes HRK1, CASP3, and CASP8 Consistent with reduced gene expression, the pro-apoptotic gene loci are less accessible in LLPCs. Of the pro-survival genes, only BCL2 is concordant in gene up-regulation and loci accessibility. Using a novel in vitro human BM mimetic, we show that blood ASCs undergo similar morphological and molecular changes that resemble ex vivo BM LLPCs. Overall, our study demonstrates that early-minted blood ASCs in the BM microniche must undergo morphological, transcriptional, and epigenetic changes to mature into apoptotic-resistant LLPCs.
Highlights
Human long-lived plasma cells (LLPCs) provide neutralizing antibodies during infection and can safeguard against subsequent encounters for a lifetime (Amanna et al, 2007; Halliley et al, 2015)
Cellular processes that are important for LLPC maturation included protein export, autophagy, and apoptosis (Fig 2F). These results show that human blood Antibody secreting cells (ASCs) subsets have significantly different transcriptional profiles compared with BM ASCs indicating blood ASCs undergo transcriptional changes to become a LLPC
It is well established that human LLPC reside in the BM, the debate continues whether LLPC merely migrate to their survival niches and take up residence or undergo further transformation once in the BM locale
Summary
Human long-lived plasma cells (LLPCs) provide neutralizing antibodies during infection and can safeguard against subsequent encounters for a lifetime (Amanna et al, 2007; Halliley et al, 2015). These cells are quiescent, terminally differentiated, non-dividing, and persist after infection or vaccination in the BM in humans, mice, and nonhuman primates (Slifka et al, 1998; Halliley et al, 2015; Hammarlund et al, 2017). Nascent blood ASCs migrate to the BM in multiple compartments early after vaccination to be located only in the LLPC compartment years later
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