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Intrinsically determined turnover underlies broad heterogeneity in plasma-cell lifespan

ABSTRACT: Antibody persistence frequently determines the longevity of immunity, yet the mechanisms that set antibody-producing plasma cell turnover rates are unestablished. While it is proposed that new plasma cells displace existing ones in competition for specialised survival niches, it is also possible that the spontaneous loss of existing plasma cells frees niches thereby creating opportunities for recruitment, possibilities with quite different implications for maximising antibody production and persistence. Here, using a genetic reporter to timestamp plasma cells, we define the distribution, phenotype, transcriptional program and population structure of long-lived plasma cells and calculate turnover dynamics. We show that the attributes of longevity are acquired and that turnover of long-lived plasma cells at homeostasis is unaffected by the absence of B cells, indicating that the mechanism of turnover is independent of competition. We propose that understanding plasma cell population dynamics may allow their manipulation to achieve specific outcomes.

ORGANISM(S): Mus musculus

PROVIDER: GSE196924 | GEO | 2023/05/09

REPOSITORIES: GEO

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Intrinsically determined turnover underlies broad heterogeneity in plasma-cell lifespan

Project description:Antibody persistence frequently determines the longevity of immunity, yet the mechanisms that set antibody-producing plasma cell turnover rates are unestablished. While it is proposed that new plasma cells displace existing ones in competition for specialised survival niches, it is also possible that the spontaneous loss of existing plasma cells frees niches thereby creating opportunities for recruitment, possibilities with quite different implications for maximising antibody production and persistence. Here, using a genetic reporter to timestamp plasma cells, we define the distribution, phenotype, transcriptional program and population structure of long-lived plasma cells and calculate turnover dynamics. We show that the attributes of longevity are acquired and that turnover of long-lived plasma cells at homeostasis is unaffected by the absence of B cells, indicating that the mechanism of turnover is independent of competition. We propose that understanding plasma cell population dynamics may allow their manipulation to achieve specific outcomes.

2023-05-09 | GSE207979 | GEO

Isotype-based plasma cell subsets display differential niches requirements in the bone marrow

Project description:Bone marrow long-lived plasma cells are essential for long-term protection against infection and their persistence within this organ relies on interactions with Cxcl12-expressing stromal cells that are still not clearly identified. Here, using single cell RNAseq and in silico transinteractome analyses we identified LepR+ mesenchymal cells as the stromal cell subset most likely to interact with plasma cells within the bone marrow. Moreover, we demonstrated that depending on the isotype they express, plasma cells may use different set of integrins and adhesion molecules to interact with these stromal cells. Altogether, our results constitute an unprecedented characterization of plasma cell subset stromal niches and open new avenues for the specific targeting of bone marrow plasma cells based on their isotype.

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Transcript profile comparison of Zbtb20-sufficient and Zbtb20-deficient polyclonal bone marrow plasma cells

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Project description:Antibody-secreting plasma cells (PCs) are generated in secondary lymphoid organs, but are reported to reside in an emerging range of anatomical sites. Analysis of the transcriptome of different tissue-resident (Tr)PC populations revealed that they each have their own transcriptional signature indicative of functional adaptation to the host tissue environment. In contrast to expectation, all TrPCs were extremely long-lived, regardless of their organ of residence, with the longevity influenced by intrinsic factors like the immunoglobulin isotype. This study reveals that extreme longevity is an intrinsic property of TrPCs whose transcriptome is imprinted by signals received both at the site of induction and within the tissue of residence.

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Transcript profile comparison of Zbtb20-sufficient and Zbtb20-deficient polyclonal bone marrow plasma cells

Project description:ZBTB20 is an adjuvant-specific factor for long-term antibody responses. This factor is critical for maintaining long-lived plasma cells in alum-adjuvanted antibody responses but is dispensable for TLR ligand-adjuvanted responses. To identify the functions of ZBTB20 in long-lived plasma cells, we performed microarray analysis on Zbtb20-sufficient and Zbtb20-deficient polyclonal bone marrow plasma cells under the assumption that ZBTB20 regulates relevant targets in all long-lived plasma cells, irrespective of their mode of formation. Chimeras were generated using Zbtb20-sufficient (WT) or Zbtb20-deficient (TRAP) E14.5 fetal livers. 3-4 months after reconstitution, donor bone marrow B220low/-CD138+ cells (4 replicates per genotype) were purified via FACS for microarray. In total, 8 samples, 4 for each genotype, were included in this study.

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mTOR has distinct functions in generating versus sustaining humoral immunity

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2016-09-20 | GSE87035 | GEO

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