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Permanent URI for this collectionhttps://gupea-staging.ub.gu.se/handle/2077/72254

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    Limited access to antigen drives generation of early B cell memory while restraining the plasmablast response
    (2021) Glaros; Emmanouilidi, Aikaterini; Angeletti, Davide; Et.al
    Cell fate decisions during early B cell activation determine the outcome of responses to pathogens and vaccines. We examined the early B cell response to T-dependent antigen in mice by single-cell RNA sequencing. Early after immunization, a homogeneous population of activated precursors (APs) gave rise to a transient wave of plasmablasts (PBs), followed a day later by the emergence of germinal center B cells (GCBCs). Most APs rapidly exited the cell cycle, giving rise to non-GC-derived early memory B cells (eMBCs) that retained an AP-like transcriptional profile. Rapid decline of antigen availability controlled these events; provision of excess antigen precluded cell cycle exit and induced a new wave of PBs. Fate mapping revealed a prominent contribution of eMBCs to the MBC pool. Quiescent cells with an MBC phenotype dominated the early response to immunization in primates. A reservoir of APs/eMBCs may enable rapid readjustment of the immune response when failure to contain a threat is manifested by increased antigen availability.
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    Temporal dynamics of persistent germinal centers and memory B cell differentiation following respiratory virus infection
    (2022) Yewdell, W. T.; Smolkin; Belcheva; Mendoza; Michaels; Cols; Angeletti, Davide; Yewdell; Chaudhuri
    Following infection or immunization, memory B cells (MBCs) and long-lived plasma cells provide humoral immunity that can last for decades. Most principles of MBC biology have been determined with hapten-protein carrier models or fluorescent protein immunizations. Here, we examine the temporal dynamics of the germinal center (GC) B cell and MBC response following mouse influenza A virus infection. We find that antiviral B cell responses within the lung-draining mediastinal lymph node (mLN) and the spleen are distinct in regard to duration, enrichment for antigen-binding cells, and class switching dynamics. While splenic GCs dissolve after 6 weeks post-infection, mLN hemagglutinin-specific (HA(+)) GCs can persist for 22 weeks. Persistent GCs continuously differentiate MBCs, with "peak"and "late"GCs contributing equal numbers of HA(+) MBCs to the long-lived compartment. Our findings highlight critical aspects of persistent GC responses and MBC differentiation following respiratory virus infection with direct implications for developing effective vaccination strategies.
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    Single-cell BCR and transcriptome analysis after influenza infection reveals spatiotemporal dynamics of antigen-specific B cells
    (2022) Mathew, Nimitha Rose; Jayanthan, Jayalal; Smirnov, Ilya; Robinson, Jonathan L; Axelsson, Hannes; Sowdamini Nakka, Sravya; Emmanouilidi, Aikaterini; Czarnewski, Paulo; Yewdell, William T; Schön, Karin; Lebrero-Fernandez, Cristina; Bernasconi, Valentina; Rodin, William; Harandi, Ali M; Lycke, Nils Y; Borcherding, Nicholas; Yewdell, Jonathan W; Greiff, Victor; Bemark, Mats; Angeletti, Davide
    B cell responses are critical for antiviral immunity. However, a comprehensive picture of antigen-specific B cell differentiation, clonal proliferation, and dynamics in different organs after infection is lacking. Here, by combining single-cell RNA and B cell receptor (BCR) sequencing of antigen-specific cells in lymph nodes, spleen, and lungs after influenza infection in mice, we identify several germinal center (GC) B cell subpopulations and organ-specific differences that persist over the course of the response. We discover transcriptional differences between memory cells in lungs and lymphoid organs and organ-restricted clonal expansion. Remarkably, we find significant clonal overlap between GC-derived memory and plasma cells. By combining BCR-mutational analyses with monoclonal antibody (mAb) expression and affinity measurements, we find that memory B cells are highly diverse and can be selected from both low- and high-affinity precursors. By linking antigen recognition with transcriptional programming, clonal proliferation, and differentiation, these finding provide important advances in our understanding of antiviral immunity.