Generation of human long-lived plasma cells by developmentally regulated epigenetic imprinting

• Type of Material: Article
• Authors: Chester J Joyner, Emory University; Ariel M Ley, Emory University; Doan Nguyen, Emory University; Mohammad Ali, Emory University; Alessia Corrado, Emory University; Christopher Tipton, Emory University; Christopher Scharer, Emory University; Tian Mi, Emory University; Matthew Woodruff, Emory University; Jennifer Hom, Emory University; Jeremy Boss, Emory University; Meixue Duan, Georgia Institute of Technology; Greg Gibson, Georgia Institute of Technology; Danielle Roberts, Emory University; Joel Andrews, Emory University; Sagar Lonial, Emory University; Inaki Sanz, Emory University; Eun-Hyung F Lee, Emory University
• Language: English
• Date: 2022-03-01
• Publisher: LIFE SCIENCE ALLIANCE LLC
• Publication Version: Final Published Version
• Copyright Statement: © 2021 Joyner et al.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.26508/lsa.202101285
• Title of Journal or Parent Work: LIFE SCIENCE ALLIANCE
• Volume: 5
• Issue: 3
• Grant/Funding Information: National Institutes of Health/National Institute of Allergy and Infectious Diseases: 1R01AI121252, 1P01AI125180, U01AI141993, U54CA260563, U19AI110483, R37AI049660, T32AI070081, and the Bill & Melinda Gates Foundation Grant INV-002351.
• Keywords: SURVIVAL; BLIMP-1; Life Sciences & Biomedicine; Life Sciences & Biomedicine - Other Topics; MCL-1; RESPONSIVENESS; Biology; BLOOD; EXPRESSION; HUMORAL IMMUNITY; Science & Technology
• Research Categories: Health Sciences, Immunology; Health Sciences, Oncology

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.