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Maintenance and functional regulation of immune memory to COVID-19 vaccines in tissues

ABSTRACT: Memory T and B cells in lymphoid and mucosal tissues maintain long-term protection, though their generation following vaccination remains challenging to assess in humans. Here, we investigated immune memory generated to COVID-19 mRNA vaccines across blood, lymphoid organs, and lungs from 42 vaccinated organ donors aged 23-86, of whom 57% were previously infected with SARS-CoV-2. Using high-dimensional profiling, we reveal that Spike (S)-reactive memory T cells distribute in lymphoid organs and lungs, variably express tissue resident markers based on infection history, and exhibit site-specific compositions of effector and regulatory memory T cells. S-reactive B cells are mostly class-switched memory cells localized to lymphoid organs correlating with circulating antibodies. Importantly, tissue memory T cells are more stably maintained post-vaccination and over age and exhibit a bias towards regulatory cell functional profiles compared to circulating populations. Our results show that mRNA vaccines can induce heterogeneous memory populations across sites for protection and controlling immune pathology.

ORGANISM(S): Homo sapiens

PROVIDER: GSE261278 | GEO | 2024/11/06

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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Maintenance and functional regulation of immune memory to COVID-19 vaccines in tissues

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