Single-cell BCR and transcriptome analysis after influenza infection reveals spatiotemporal dynamics of antigen-specific B cells

Mathew, Nimitha R.; Jayanthan, Jayalal K.; Смирнов, И. В.; Robinson, Jonathan L.; Axelsson, Hannes; Nakka, Sravya Sowdamini; Emmanouilidi, Aikaterini; Czarnewski, Paulo; Yewdell, William T.; Schön, Karin; Lebrero‐Fernández, Cristina; Bernasconi, Valentina; Rodin, William; Harandi, Ali M.; Lycke, Nils; Borcherding, Nicholas; Yewdell, Jonathan W.; Greiff, Victor; Bemark, Mats; Angeletti, Davide

doi:10.1016/j.celrep.2021.109286

Cited by 84 publications

(76 citation statements)

References 88 publications

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“…These may be comprised of early germinal center B cells and short-lived plasmablasts, the latter being generated within the first days after an immunization or infection and are considered as transient precursors of plasma cells ( 34–36 ). A recent study reported similar findings of highly expanded germinal center B cells in draining lymph nodes seven days after influenza infection in mice ( 10 ). Overlap analysis of the most expanded clones revealed distinct physiological axes: inguinal and axillary lymph nodes from the left side shared the majority of their expanded clones, whereas the same was true for right-side lymph nodes, with minimal overlap across left and right lymph nodes.…”

Section: Discussionsupporting

confidence: 66%

“…Yang et al reported shared antibody repertoires across human tissues and inferred antigen-specificity based on similarity to previously reported pathogen-specific antibody sequences ( 8 ). In the context of mice, Mathew et al analyzed antigen-specific B cells in the draining lymph nodes, spleen and lungs after influenza infection, which revealed distinct organ-specific antibody repertoire features ( 10 ).…”

Section: Introductionmentioning

confidence: 99%

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The Physiological Landscape and Specificity of Antibody Repertoires

Csepregi

Hoehn

Neumeier

et al. 2021

Preprint

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Diverse antibody repertoires spanning multiple lymphoid organs (e.g., bone marrow, spleen, lymph nodes) form the foundation of protective humoral immunity. Changes in their composition across lymphoid organs are a consequence of B-cell selection and migration events leading to a highly dynamic and unique physiological landscape of antibody repertoires upon antigenic challenge (e.g., vaccination). However, to what extent B cells encoding identical or similar antibody sequences (clones) are distributed across multiple lymphoid organs and how this is shaped by the strength of a humoral response, remains largely unexplored. Here, we performed an in-depth systems analysis of antibody repertoires across multiple distinct lymphoid organs of immunized mice, and discovered that organ-specific antibody repertoire features (e.g., germline V-gene usage and clonal expansion profiles) equilibrated upon a strong humoral response (multiple immunizations and high serum titers). This resulted in a surprisingly high degree of repertoire consolidation, characterized by highly connected and overlapping B-cell clones across multiple lymphoid organs. Finally, we revealed distinct physiological axes indicating clonal migrations and showed that antibody repertoire consolidation directly correlated with antigen-specificity. Our study uncovered how a strong humoral response resulted in a more uniform but redundant physiological landscape of antibody repertoires, indicating that increases in antibody serum titers were a result of synergistic contributions from antigen-specific B-cell clones distributed across multiple lymphoid organs. Our findings provide valuable insights for the assessment and design of vaccine strategies.

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Section: Discussionsupporting

confidence: 66%

Section: Introductionmentioning

confidence: 99%

The Physiological Landscape and Specificity of Antibody Repertoires

Csepregi

Hoehn

Neumeier

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…IgA isotype switched ASCs were maintained in the URT at least 8 weeks post infection, while the lung contained both IgA and IgG isotype switched ASCs ( 22 ). Detailed clonal analysis of the B cell responses to influenza infection also demonstrated that infection elicits a widely disseminated B cell response ( 60 ). This clonally diverse response includes a subset of influenza-specific B memory cells generated in SLO that migrate to the lung and become resident memory cells ( 60 ).…”

Section: Defining the Contributions Of Local And Systemic Antibody Responsesmentioning

confidence: 99%

“…Detailed clonal analysis of the B cell responses to influenza infection also demonstrated that infection elicits a widely disseminated B cell response ( 60 ). This clonally diverse response includes a subset of influenza-specific B memory cells generated in SLO that migrate to the lung and become resident memory cells ( 60 ). These data suggest that while there is relatively stable output of plasmablasts and memory B cells from the germinal center reaction, there is a kinetic window for establishing tissue resident memory in the lung.…”

Section: Defining the Contributions Of Local And Systemic Antibody Responsesmentioning

confidence: 99%

“…These data suggest that while there is relatively stable output of plasmablasts and memory B cells from the germinal center reaction, there is a kinetic window for establishing tissue resident memory in the lung. B cells generated in the lung draining lymph node can home to the lung up to 28 days post infection and cells derived from the spleen can home to the lung for up to 14 days post infection ( 60 ). Others have shown that Brm is durable, persisting for at least 5 months post infection ( 61 ).…”

Section: Defining the Contributions Of Local And Systemic Antibody Responsesmentioning

confidence: 99%

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Potentiating Lung Mucosal Immunity Through Intranasal Vaccination

Nelson

Sant

2021

Front. Immunol.

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Yearly administration of influenza vaccines is our best available tool for controlling influenza virus spread. However, both practical and immunological factors sometimes result in sub-optimal vaccine efficacy. The call for improved, or even universal, influenza vaccines within the field has led to development of pre-clinical and clinical vaccine candidates that aim to address limitations of current influenza vaccine approaches. Here, we consider the route of immunization as a critical factor in eliciting tissue resident memory (Trm) populations that are not a target of current licensed intramuscular vaccines. Intranasal vaccination has the potential to boost tissue resident B and T cell populations that reside within specific niches of the upper and lower respiratory tract. Within these niches, Trm cells are poised to respond rapidly to pathogen re-encounter by nature of their anatomic localization and their ability to rapidly deliver anti-pathogen effector functions. Unique features of mucosal immunity in the upper and lower respiratory tracts suggest that antigen localized to these regions is required for the elicitation of protective B and T cell immunity at these sites and will need to be considered as an important attribute of a rationally designed intranasal vaccine. Finally, we discuss outstanding questions and areas of future inquiry in the field of lung mucosal immunity.

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Ezh2 Knockout in B Cells Impairs Plasmablast Differentiation and Ameliorates Lupus‐like Disease in MRL/lpr Mice

Zheng

Dozmorov

Strohlein

et al. 2023

Arthritis & Rheumatology

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Objectives EZH2 regulates B cell development and differentiation. We previously demonstrated increased EZH2 expression in peripheral blood mononuclear cells from lupus patients. The goal of this study was to evaluate the role of EZH2 expression in B cells in the pathogenesis of lupus. Methods We generated an MRL/lpr mouse with floxed Ezh2, which was crossed with CD19‐Cre mice to examine the effect of B cell EZH2 deficiency in MRL/lpr lupus‐prone mice. Differentiation of B cells was assessed using flow cytometry. Single‐cell RNA sequencing and single‐cell B cell receptor sequencing were performed. In vitro B cell culture with an X‐box binding protein 1 (XBP1) inhibitor was performed. EZH2 and XBP1 messenger RNA levels in CD19+ B cells isolated from lupus patients and healthy controls were analyzed. Results We show that Ezh2 deletion in B cells significantly decreased autoantibody production and improved glomerulonephritis. B cell development was altered in the bone marrow and spleen of EZH2‐deficient mice. Differentiation of germinal center B cells and plasmablasts was impaired. Single‐cell RNA sequencing showed that XBP1, a key transcription factor in B cell development, is down‐regulated in the absence of EZH2. Inhibiting XBP1 in vitro impairs plasmablast development similar to EZH2 deficiency in mice. Single‐cell B cell receptor RNA sequencing revealed defective immunoglobulin class‐switch recombination in EZH2‐deficient mice. In human lupus B cells, we observed a strong correlation between EZH2 and XBP1 messenger RNA expression levels. Conclusion EZH2 overexpression in B cells contributes to disease pathogenesis in lupus.

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Single-cell BCR and transcriptome analysis after influenza infection reveals spatiotemporal dynamics of antigen-specific B cells

Cited by 84 publications

References 88 publications

The Physiological Landscape and Specificity of Antibody Repertoires

The Physiological Landscape and Specificity of Antibody Repertoires

Potentiating Lung Mucosal Immunity Through Intranasal Vaccination

Ezh2 Knockout in B Cells Impairs Plasmablast Differentiation and Ameliorates Lupus‐like Disease in MRL/lpr Mice

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