RT Journal Article
SR Electronic
T1 Generation of human long-lived plasma cells by developmentally regulated epigenetic imprinting
JF Life Science Alliance
JO Life Sci. Alliance
FD Life Science Alliance LLC
SP e202101285
DO 10.26508/lsa.202101285
VO 5
IS 3
A1 Chester J Joyner
A1 Ariel M Ley
A1 Doan C Nguyen
A1 Mohammad Ali
A1 Alessia Corrado
A1 Christopher Tipton
A1 Christopher D Scharer
A1 Tian Mi
A1 Matthew C Woodruff
A1 Jennifer Hom
A1 Jeremy M Boss
A1 Meixue Duan
A1 Greg Gibson
A1 Danielle Roberts
A1 Joel Andrews
A1 Sagar Lonial
A1 Inaki Sanz
A1 F Eun-Hyung Lee
YR 2022
UL https://www.life-science-alliance.org/content/5/3/e202101285.abstract
AB 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.