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Two distinct durable human switched memory B cell populations are induced by vaccination and infection

ABSTRACT: The traditional definition of memory lymphocytes encompasses antigen-experienced, durable subsets that persist in the absence of antigen and are capable of responding to the antigen on subsequent encounters. We examined the relative durability of eight different non-overlapping class-switched human B cell sub-populations (excluding plasmablasts) that together encompass 100% of all human class switched B cells and identified only two long-lived B cell populations that persist after vaccination in the relative absence of their cognate antigen. In addition to canonical switched memory B cells (SWM) with an IgD- CD27+ CXCR5+ phenotype, a second, non-canonical but distinct memory population of IgD- CD27- CXCR5+ (double negative 1, DN1) B cells is also durable. Beyond surface phenotyping, DN1 memory B cells intriguingly exhibit lower levels of replacement mutations in complementarity determining as well as framework regions of their B cell receptors and have longer CDRH3 sequences relative to canonical SWM B cells. This non-canonical, human memory B cell subset is distinguished by a distinct TP63 driven transcriptional signature that has been linked to extended cell survival and these B cells persist in the circulation at least as long as canonical SWM B cells. Non-canonical human DN1 memory B cells therefore represent a second, distinct, durable, less somatically hypermutated, class-switched human memory B cell subset defined by a unique transcriptomic signature, that likely arises outside germinal centers and may have evolved to preserve immunological breadth.

ORGANISM(S): Homo sapiens

PROVIDER: GSE278378 | GEO | 2025/03/20

REPOSITORIES: GEO

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Project description:Memory B cells represent one of the pillar of humoral protection and are found in the circulation and secondary lymphoid organs several decades after initial pathogen or vaccine encounter. The exact cellular and biological mechanisms allowing long-term survival of quiescent cells in such a fluctuating microenvironment remain poorly understood. Assessing the true longevity of human memory B cells against common pathogens is, in most settings, hindered by the possibility for any given individual to re-encounter them during his lifetime. Smallpox, officially declared eradicated in 1980 (Fenner WHO 1988), represents one notable exception. Alongside smallpox eradication, anti-smallpox vaccination, based on the live Vaccinia virus, was progressively discontinued during the 1970s. As such, any detectable anti-vaccinia memory B cell in an individual post 2010 would likely have been generated more than 40 years ago, without any re-stimulation with the immunizing antigen during that timeframe. Anti-vaccinia antibodies serum titers remain stable in human for more than 80 years after first vaccination (Amanna NEJM 2007, PMID: 17989383), with several identified immunodominant epitopes including the envelope glycoprotein B5R (Lantto J Virol 2011, PMID: 21147924). Anti-vaccinia memory B cells have similarly been followed longitudinally in the blood for up to 65 years post vaccination (Amanna NEJM 2007, PMID: 17989383 ; Crotty JI 2003, PMID : 14607890) and, following a contraction phase taking place in the first couple of years after immunization, reach a remarkably stable plateau that last for decades at around 0.1% of total circulating IgG+ memory B cells. Functional analysis of such long-lived memory B cells, however, is still lacking. As a proxy to study long-lived memory B cells, IgG+ switched memory B cells specific for the immunodominant Vaccinia antigen B5R (B5R+ IgG+ memory B cells) were sorted and analyzed by scRNAseq from the spleen of six organ donors, collected between 2015 and 2018. For all donors, B5R+ IgG+ memory B cells were sorted alongside total IgG+ memory B cells (live IgD-CD27+IgG+CD20+CD3-CD14-CD16-) and naïve B cells (live IgD+CD27-CD38-CD24-CD20+CD3-CD14-CD16-). Single-cell mRNA sequencing was performed according to an adapted version of the SORT-seq protocol (Muraro et al., 2016, PMID: 27693023), with cDNA libraries generation, sequencing and reads alignment performed at Single Cell Discoveries (Utrecht, Netherlands).

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Two distinct durable human switched memory B cell populations are induced by vaccination and infection

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