Memory persistence and differentiation into antibody-secreting cells accompanied by positive selection in longitudinal BCR repertoires
- Skolkovo Institute of Science and Technology, Russian Federation
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Federation
- Pirogov Russian National Research Medical University, Russian Federation
Abstract
The stability and plasticity of B cell-mediated immune memory ensures the ability to respond to the repeated challenges. We have analyzed the longitudinal dynamics of immunoglobulin heavy chain repertoires from memory B cells, plasmablasts, and plasma cells from the peripheral blood of generally healthy volunteers. We reveal a high degree of clonal persistence in individual memory B cell subsets, with inter-individual convergence in memory and antibody-secreting cells (ASCs). ASC clonotypes demonstrate clonal relatedness to memory B cells, and are transient in peripheral blood. We identify two clusters of expanded clonal lineages with differing prevalence of memory B cells, isotypes, and persistence. Phylogenetic analysis revealed signs of reactivation of persisting memory B cell-enriched clonal lineages, accompanied by new rounds of affinity maturation during proliferation and differentiation into ASCs. Negative selection contributes to both persisting and reactivated lineages, preserving the functionality and specificity of BCRs to protect against current and future pathogens.
Data availability
Sequencing data have been deposited in the ArrayExpress database (www.ebi.ac.uk/arrayexpress, acc. num. E-MTAB-11193). The code for repertoire analysis is available at https://github.com/amikelov/igh_subsets; the code for clonal lineage analysis is available at https://github.com/EvgeniiaAlekseeva/Clonal_group_analysis
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Naive B-cell receptor heavy chain repertoire of celiac patients and healthy controlsEuropean Nucleotide Archive, PRJEB26509.
Article and author information
Author details
Dmitriy M Chudakov
Funding
Ministry of Science and Higher Education of the Russian Federation (075-15-2020-807)
- Dmitriy M Chudakov
Russian Foundation for Basic Research (20-34-90153)
- Evgeniia I Alekseeva
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Human subjects: Informed consent was obtained from each donor. The study was approved by the Local Ethical Committee of Pirogov Russian National Research Medical University, Moscow, Russia (abstract #190 18 Nov 2019).
Copyright
© 2022, Mikelov et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Memory persistence and differentiation into antibody-secreting cells accompanied by positive selection in longitudinal BCR repertoires
eLife 11:e79254.
https://doi.org/10.7554/eLife.79254
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Preeclampsia (PE), a major cause of maternal and perinatal mortality with highly heterogeneous causes and symptoms, is usually complicated by gestational diabetes mellitus (GDM). However, a comprehensive understanding of the immune microenvironment in the placenta of PE and the differences between PE and GDM is still lacking. In this study, cytometry by time of flight indicated that the frequencies of memory-like Th17 cells (CD45RA−CCR7+IL-17A+CD4+), memory-like CD8+ T cells (CD38+CXCR3−CCR7+Helios−CD127−CD8+) and pro-inflam Macs (CD206−CD163−CD38midCD107alowCD86midHLA-DRmidCD14+) were increased, while the frequencies of anti-inflam Macs (CD206+CD163−CD86midCD33+HLA-DR+CD14+) and granulocyte myeloid-derived suppressor cells (gMDSCs, CD11b+CD15hiHLA-DRlow) were decreased in the placenta of PE compared with that of normal pregnancy (NP), but not in that of GDM or GDM&PE. The pro-inflam Macs were positively correlated with memory-like Th17 cells and memory-like CD8+ T cells but negatively correlated with gMDSCs. Single-cell RNA sequencing revealed that transferring the F4/80+CD206− pro-inflam Macs with a Folr2+Ccl7+Ccl8+C1qa+C1qb+C1qc+ phenotype from the uterus of PE mice to normal pregnant mice induced the production of memory-like IL-17a+Rora+Il1r1+TNF+Cxcr6+S100a4+CD44+ Th17 cells via IGF1–IGF1R, which contributed to the development and recurrence of PE. Pro-inflam Macs also induced the production of memory-like CD8+ T cells but inhibited the production of Ly6g+S100a8+S100a9+Retnlg+Wfdc21+ gMDSCs at the maternal–fetal interface, leading to PE-like symptoms in mice. In conclusion, this study revealed the PE-specific immune cell network, which was regulated by pro-inflam Macs, providing new ideas about the pathogenesis of PE.
