Limited access to antigen drives generation of early B cell memory while restraining the plasmablast response

Glaros, Vassilis; Rauschmeier, René; Av, Artemov; Reinhardt, Annika; Ols, Sebastian; Emmanouilidi, Aikaterini; Gustafsson, Charlotte; You, Yun; Mirabello, Claudio; Björklund, Åsa K.; Perez, Laurent; King, Neil P.; Månsson, Robert; Angeletti, Davide; Loré, Karin; Adameyko, Igor; Busslinger, Meinrad; Kreslavsky, Taras

doi:10.1016/j.immuni.2021.08.017

Cited by 62 publications

(70 citation statements)

References 89 publications

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“…5C, D ) [ 56 ]. On the other hand, clusters 2 and 3, in 4T1 and EMT6 respectively, had a similar transcriptional profile attributable to a proliferative B cell population, as confirmed by the expression of Mki67 and Mcm5 genes [ 39 , 57 ]. Similarly, cluster 4 and cluster 7, in 4T1 and EMT6 respectively, highly expressed Cd38 gene but not Mki67 (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Also depending on the results and the expression of known gene markers the granularity was chosen accordingly (0.2 and 0.3 for Cd4 and Cd8 respectively in 4T1 cell line, 0.1 and 0.2 for B in the 4T1 and EMT6 cell line respectively, 0.4 for macrophages in EMT6 cell line). The sub-clusters cell assignment was performed only with manual curation by choosing a known set of genes from relevant studies that focus on the same cell populations [ 39 – 42 ] in similar mouse models and evaluating their expression in the sub-clusters.…”

Section: Methodsmentioning

confidence: 99%

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A single-cell transcriptomic landscape of innate and adaptive intratumoral immunity in triple negative breast cancer during chemo- and immunotherapies

et al. 2022

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Breast cancer (BC) constitutes a major health problem worldwide, making it the most common malignancy in women. Current treatment options for BC depend primarily on histological type, molecular markers, clinical aggressiveness and stage of disease. Immunotherapy, such as αPD-1, have shown combinatorial clinical activity with chemotherapy in triple negative breast cancer (TNBC) delineating some therapeutic combinations as more effective than others. However, a clear overview of the main immune cell populations involved in these treatments has never been provided.Here, an assessment of the immune landscape in the tumor microenvironment (TME) of two TNBC mouse models has been performed using single-cell RNA sequencing technology. Specifically, immune cells were evaluated in untreated conditions and after treatments with chemotherapy or immunotherapy used as single agents or in combination. A decrease of Treg was found in treatments with in vivo efficacy as well as γδ T cells, which have a pro-tumoral activity in mice. Focusing on Cd8 T cells, across all the conditions, a general increase of exhausted-like Cd8 T cells was confirmed in pre-clinical treatments with low efficacy and an opposite trend was found for the proliferative Cd8 T cells. Regarding macrophages, M2-like cells were enriched in treatments with low efficacy while M1-like macrophages followed an opposite trend. For both models, similar proportions of B cells were detected with an increase of proliferative B cells in treatments involving cisplatin in combination with αPD-1. The fine-scale characterization of the immune TME in this work can lead to new insights on the diagnosis and treatment of TNBC.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

A single-cell transcriptomic landscape of innate and adaptive intratumoral immunity in triple negative breast cancer during chemo- and immunotherapies

et al. 2022

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“…Before entering the GC, activated B cells compete for follicular helper T (Tfh) cell help at the T-B border based on the amount of peptide-MHC class II (MHC-II) presented by the B cells to the Tfh cells. Hence, the success of B cells competing for early Tfh help depends on their frequency and their B cell receptor (BCR) affinity for antigens (14)(15)(16)(17). Rare B cells, such as broadly neutralizing antibody (bnAb) precursor B cells with low affinity (18), may be excluded from entering the GC at this early Tfh cell checkpoint.…”

Section: Positive Selection Of High-affinity Gc B Cellsmentioning

confidence: 99%

Generation of High Quality Memory B Cells

2022

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Protection against pathogen re-infection is mediated, in large part, by two humoral cellular compartments, namely, long-lived plasma cells and memory B cells. Recent data have reinforced the importance of memory B cells, particularly in response to re-infection of different viral subtypes or in response with viral escape mutants. In regard to memory B cell generation, considerable advancements have been made in recent years in elucidating its basic mechanism, which seems to well explain why the memory B cells pool can deal with variant viruses. Despite such progress, efforts to develop vaccines that induce broadly protective memory B cells to fight against rapidly mutating pathogens such as influenza virus and HIV have not yet been successful. Here, we discuss recent advances regarding the key signals and factors regulating germinal center-derived memory B cell development and activation and highlight the challenges for successful vaccine development.

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“…However, Price et al (37) demonstrated the feasibility to molecularly characterize ASC following intracellular staining for both antibody isotype as well as antibody specificity using tetramer constructs of antigens bound to fluorophore-conjugated streptavidin. Alternatively, early IgG-expressing ASC (IgG-ASC) often continue to bear their antibodies at the cell membrane, and surface staining for antibody isotype and antigen-specificity with tetramers offers a simpler method for isolating such IgG-ASC, though represents a restricted view of the whole IgG-ASC population (38,39). Flow cytometry is also a valuable tool for scouting potential novel markers of ASC subsets (40).…”

Section: Cytometry-based Assaysmentioning

confidence: 99%

“…Recent advances on ASC characterization using RNAseq, ATAC-seq and ChIP-seq have been reviewed elsewhere (86), as well as molecular mechanisms leading to plasma cell differentiation from the germinal center reaction (87). Glaros et al (38) highlight the capacity for scRNAseq to identify B cell subsets and observe shifts in differentiation, identifying antigen availability as a key regulator of the plasmablast response.…”

Section: Molecular Analysesmentioning

confidence: 99%

Single-Cell Technologies for the Study of Antibody-Secreting Cells

Broketa

Bruhns

2022

Front. Immunol.

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Antibody-secreting cells (ASC), plasmablasts and plasma cells, are terminally differentiated B cells responsible for large-scale production and secretion of antibodies. ASC are derived from activated B cells, which may differentiate extrafollicularly or form germinal center (GC) reactions within secondary lymphoid organs. ASC therefore consist of short-lived, poorly matured plasmablasts that generally secrete lower-affinity antibodies, or long-lived, highly matured plasma cells that generally secrete higher-affinity antibodies. The ASC population is responsible for producing an immediate humoral B cell response, the polyclonal antibody repertoire, as well as in parallel building effective humoral memory and immunity, or potentially driving pathology in the case of autoimmunity. ASC are phenotypically and transcriptionally distinct from other B cells and further distinguishable by morphology, varied lifespans, and anatomical localization. Single cell analyses are required to interrogate the functional and transcriptional diversity of ASC and their secreted antibody repertoire and understand the contribution of individual ASC responses to the polyclonal humoral response. Here we summarize the current and emerging functional and molecular techniques for high-throughput characterization of ASC with single cell resolution, including flow and mass cytometry, spot-based and microfluidic-based assays, focusing on functional approaches of the secreted antibodies: specificity, affinity, and secretion rate.

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Limited access to antigen drives generation of early B cell memory while restraining the plasmablast response

Cited by 62 publications

References 89 publications

A single-cell transcriptomic landscape of innate and adaptive intratumoral immunity in triple negative breast cancer during chemo- and immunotherapies

A single-cell transcriptomic landscape of innate and adaptive intratumoral immunity in triple negative breast cancer during chemo- and immunotherapies

Generation of High Quality Memory B Cells

Single-Cell Technologies for the Study of Antibody-Secreting Cells

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