Follicular dendritic cells restrict interleukin-4 availability in germinal centers and foster memory B cell generation

Duan, Lihui; Liú, Dan; Chen, Hsin; Mintz, Michelle A.; Chou, Marissa; Kotov, Dmitri I.; Xu, Ying; An, Jinping; Laidlaw, Brian J.

doi:10.1016/j.immuni.2021.08.028

Cited by 65 publications

(61 citation statements)

References 92 publications

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“…In mice, it has been suggested that most pre-plasmablasts are derived from positively selected cells i.e., expressing MYC gene ( 13 , 20 ), we found among the 1,518 human MYC-positive LZ B GC -cells from Holmes et al ( 26 ) dataset that 316 (21%) and 1,202 (79%) were, respectively, positive and negative for FCER2 expression. This result was consistent with data obtained recently in mice ( 24 ). Altogether, these data suggest that FCER2 -negative LZ B GC -cells were either unable to express FCER2 or had not received sufficient Tfh cell help to express it.…”

Section: Resultssupporting

confidence: 94%

“…In B cells, CD23 expression is induced by Tfh-derived cytokines in general and by IL-4/STAT6 signaling in particular. CD23 + and CD23 -LZ B GC -cells expressed similar levels of IL-21 and IL-4 receptors, CD40 and Ki-67, however, we found a significantly higher proportion of CCR6 + cells in the CD23 + subset consistent with Duan et al (24) in mice. These cells could correspond to memory B cell precursors (Figure 1E and Supplemental Figure S1F) (25).…”

Section: Results In Gcs Only a Small Proportion Of B Cells Expresses The Cd23 Markersupporting

confidence: 91%

“…In addition, our study confirmed previous data by showing that LZ stromal FDCs express very high levels of the CD23 receptor (22,23). Complementing very recently published data from Cyster's team showing that FDC restricted IL-4 availability in the GC (24) and our work revealing the expression of IL-4 receptor and CD40 by FDCs (39), it is tempting to speculate that FDCs activate CD23 expression by trapping molecules produced by Tfh cells in the LZ and then titrating them. In such a case, the LZ B GC -cells require effective, lasting contact with Tfh cells for activation leading notably in B cells by the recruitment of the IL-4/STAT6 signaling and CD23 expression (19).…”

Section: Discussionsupporting

confidence: 89%

“…Overall, the CD23 marker might be of value in answering questions about the differentiation of normal B GC -cells. Based on extensive data in the literature including our previously published data ( 14 , 50 , 51 ) and present results complemented by explorations on previous scRNA-seq ( 26 ) as well as recent results of Duan et al ( 24 ), we propose an instructive model of the maturation and fate of human B GC -cells in LZ ( Figure 8 ). The majority of B GC -cells are CD23-negative, progress in an affinity-based proliferation and compete for Tfh help leading to a productive IL-4/pSTAT6 response.…”

Section: Discussionsupporting

confidence: 65%

“…Fit cells proliferate, retrieve Ag deposited on follicular dendritic cells (FDCs) and receive survival signals from stromal cells (top-middle part). Note that FDCs express IL-4R and may take available IL-4 cytokine - in a non-directed manner [IL-4 broadcasting as called in ( 24 )] – produced by Tfh. Both, high and low-affinity cells process Ag and present - in proportion to its affinity - peptide-MHC complex which supports the interaction with cognate Tfh and the delivery of crucial molecules including IL-21, CD40L and IL-4 leading to pSTAT6 expression (right-middle part).…”

Section: Discussionmentioning

confidence: 99%

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Committed Human CD23-Negative Light-Zone Germinal Center B Cells Delineate Transcriptional Program Supporting Plasma Cell Differentiation

et al. 2021

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B cell affinity maturation occurs in the germinal center (GC). Light-zone (LZ) GC B cells (BGC-cells) interact with follicular dendritic cells (FDCs) and compete for the limited, sequential help from T follicular helper cells needed to escape from apoptosis and complete their differentiation. The highest-affinity LZ BGC-cells enter the cell cycle and differentiate into PCs, following a dramatic epigenetic reorganization that induces transcriptome changes in general and the expression of the PRDM1 gene in particular. Human PC precursors are characterized by the loss of IL-4/STAT6 signaling and the absence of CD23 expression. Here, we studied the fate of human LZ BGC-cells as a function of their CD23 expression. We first showed that CD23 expression was restricted to the GC LZ, where it was primarily expressed by FDCs; less than 10% of tonsil LZ BGC-cells were positive. Sorted LZ BGC-cells left in culture and stimulated upregulated CD23 expression but were unable to differentiate into PCs – in contrast to cells that did not upregulate CD23 expression. An in-depth analysis (including single-cell gene expression) showed that stimulated CD23-negative LZ BGC-cells differentiated into plasmablasts and time course of gene expression changes delineates the transcriptional program that sustains PC differentiation. In particular, we identified a B cell proliferation signature supported by a transient MYC gene expression. Overall, the CD23 marker might be of value in answering questions about the differentiation of normal BGC-cells and allowed us to propose an instructive LZ BGC-cells maturation and fate model.

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Section: Resultssupporting

confidence: 94%

Section: Results In Gcs Only a Small Proportion Of B Cells Expresses The Cd23 Markersupporting

confidence: 91%

Section: Discussionsupporting

confidence: 89%

Section: Discussionsupporting

confidence: 65%

Section: Discussionmentioning

confidence: 99%

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Committed Human CD23-Negative Light-Zone Germinal Center B Cells Delineate Transcriptional Program Supporting Plasma Cell Differentiation

et al. 2021

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Memory B‐cell diversity: From early generation to tissue residency and reactivation

Reusch

Angeletti

2023

Eur J Immunol

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Memory B cells (MBCs) have a crucial function in providing an enhanced response to repeated infections. Upon antigen encounter, MBC can either rapidly differentiate to antibody secreting cells or enter germinal centers (GC) to further diversify and affinity mature. Understanding how and when MBC are formed, where they reside and how they select their fate upon reactivation has profound implications for designing strategies to improve targeted, next‐generation vaccines. Recent studies have crystallized much of our knowledge on MBC but also reported several surprising discoveries and gaps in our current understanding. Here, we review the latest advancements in the field and highlight current unknowns. In particular, we focus on timing and cues leading to MBC generation before and during the GC reaction, discuss how MBC become resident in mucosal tissues, and finally, provide an overview of factors shaping MBC fate‐decision upon reactivation in mucosal and lymphoid tissues.

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The function of γδ T cells in humoral immune responses

2023

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Follicular dendritic cells restrict interleukin-4 availability in germinal centers and foster memory B cell generation

Cited by 65 publications

References 92 publications

Committed Human CD23-Negative Light-Zone Germinal Center B Cells Delineate Transcriptional Program Supporting Plasma Cell Differentiation

Committed Human CD23-Negative Light-Zone Germinal Center B Cells Delineate Transcriptional Program Supporting Plasma Cell Differentiation

Memory B‐cell diversity: From early generation to tissue residency and reactivation

The function of γδ T cells in humoral immune responses

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