Follicular dendritic cells restrict interleukin-4 availability in germinal centers and foster memory B cell generation
TL;DR: In this article, the authors examined the contribution of interleukin (IL)-4 on B cell fate decisions in the germinal centers (GCs) and identified a subset of light zone GC B cells expressing high IL-4 receptor-a (IL4Ra) and CD23 and lacking a Myc-associated signature.
About: This article is published in Immunity.The article was published on 2021-10-12. It has received 27 citations till now. The article focuses on the topics: Memory B cell & Follicular dendritic cells.
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TL;DR: Follicular helper T (TFH) cells support germinal center formation and regulate clonal selection and differentiation of memory and antibody-secreting B cells, thus controlling antibody affinity maturation and memory.
18 citations
TL;DR: Germinal center B cells compete to be refueled by T cells but not for cyclic reentry initiation during affinity maturation, which may contribute to permitting cells of different competencies to be sustained alongside each other and allow T cell support to be provided across a dynamic range commensurate with affinity.
Abstract: Antibody affinity maturation occurs in germinal centers (GCs) through iterative rounds of somatic hypermutation and proliferation in dark zones (DZs) and selection in light zones (LZs). GC B cells exit cell cycle a number of hours before entering LZs; therefore, continued participation in responses requires that they subsequently reenter cell cycle and move back to DZs, a process known as cyclic reentry. Affinity enhancements are thought to arise by B cells having to compete to initiate cyclic reentry each time they enter LZs, with T cell help being a major determinant; however, direct proof is lacking. Using Fucci2 mice, we confirmed an association between B cell receptor affinity and the first step of cyclic reentry, S phase initiation from a resting LZ state. However, neither T cell ablation nor MHCII deletion prevented resting LZ cells from reentering cell cycle, and this late G1-S transition was also not detectably restricted by competition. In contrast, using BATF induction as exemplar, we found that T cells “refueled” LZ cells in an affinity-dependent manner that was limited by both competition and cells’ intrinsic antigen-acquiring abilities. Therefore, cyclic reentry initiation and B cell refueling are independently regulated in GCs, which may contribute to permitting cells of different competencies to be sustained alongside each other and allow T cell support to be provided across a dynamic range commensurate with affinity. We speculate that this less binary selection mechanism could help GCs nurture complex antibody maturation pathways and support the clonal diversity required for countering fast-evolving pathogens. Description Germinal center B cells compete to be refueled by T cells but not for cyclic reentry initiation during affinity maturation. When T cells aren’t so helpful Germinal center (GC) B cells undergo rounds of somatic hypermutation and clonal selection, resulting in increased antibody affinity. Clonal selection is incompletely understood but may involve GC B cells being instructed to reenter cell cycle and move from light zones to dark zones, known as “cyclic reentry.” Long et al. tested key assumptions of cyclic reentry models using Fucci2 cell cycle reporter mice in combination with approaches to modulate selection inputs. T cell depletion and MHCII deletion in GC B cells identified that T cell help is not limiting or necessary for initiation of cyclic reentry. Instead, the authors found that T cell help “refueled” GC B cells, which likely prepares them for a better life in the dark zone. These results provide new context into how GC B cells are selected.
18 citations
TL;DR: In this paper , the authors combined influenza and SARS-CoV-2 infection with fluorescent-reporter mice to identify lung resident memory B cells (MBCs) regardless of antigen specificity.
13 citations
TL;DR: In this article , the pathomechanism of atopic diseases demonstrated a pivotal role of the cytokines interleukin-4 (IL•4) and IL•13, which has spurred the development of tailored therapeutics targeting their common IL•4 receptor (IL−4R).
Abstract: Insight into the pathomechanism of atopic diseases demonstrated a pivotal role of the cytokines interleukin‐4 (IL‐4) and IL‐13, which has spurred the development of tailored therapeutics targeting their common IL‐4 receptor (IL‐4R). However, several aspects of the IL‐4R system remain ill‐defined in humans.
6 citations
TL;DR: In this paper , a population of type 2 polarized memory B cells (MBC2s) were identified as the primary reservoir of IgE memory, which is beneficial in protection against venoms and helminths.
Abstract: Allergen-specific IgE antibodies mediate allergic pathology in diseases such as allergic rhinitis and food allergy. Memory B cells (MBCs) contribute to circulating IgE by regenerating IgE-producing plasma cells upon allergen encounter. We report a population of type 2 polarized MBCs defined as CD23hi, IL-4Rαhi, CD32low at the transcriptional and surface protein levels. These “MBC2s” are enriched in IgG1 and IgG4-expressing cells, while constitutively expressing germline transcripts for IgE. Allergen-specific B cells from patients with allergic rhinitis and food allergy were enriched in MBC2s. MBC2s generated allergen specific-IgE during sublingual immunotherapy, thereby identifying these cells as the primary reservoir of IgE. The identification of MBC2s provides insights into the maintenance of IgE memory, which is detrimental in allergic diseases, but which could be beneficial in protection against venoms and helminths. One-Sentence Summary Identification of a novel memory B cell subset which holds allergen specific IgE memory.
3 citations
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TL;DR: WebLogo generates sequence logos, graphical representations of the patterns within a multiple sequence alignment that provide a richer and more precise description of sequence similarity than consensus sequences and can rapidly reveal significant features of the alignment otherwise difficult to perceive.
Abstract: WebLogo generates sequence logos, graphical representations of the patterns within a multiple sequence alignment. Sequence logos provide a richer and more precise description of sequence similarity than consensus sequences and can rapidly reveal significant features of the alignment otherwise difficult to perceive. Each logo consists of stacks of letters, one stack for each position in the sequence. The overall height of each stack indicates the sequence conservation at that position (measured in bits), whereas the height of symbols within the stack reflects the relative frequency of the corresponding amino or nucleic acid at that position. WebLogo has been enhanced recently with additional features and options, to provide a convenient and highly configurable sequence logo generator. A command line interface and the complete, open WebLogo source code are available for local installation and customization.
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2,285 citations
TL;DR: It is concluded that Stat6 plays a central role in exerting IL-4-mediated biological responses, and production of Th2 cytokines from T cells as well as IgE and IgGl responses after nematode infection were profoundly reduced.
Abstract: Interleukin-4 (IL-4) is a pleiotropic lymphokine which plays an important role in the immune system. IL-4 activates two distinct signalling pathways through tyrosine phosphorylation of Stat6, a signal transducer and activator of transcription, and of a 170K protein called 4PS. To investigate the functional role of Stat6 in IL-4 signalling, we generated mice deficient in Stat6 by gene targeting. We report here that in the mutant mice, expression of CD23 and major histocompatibility complex (MHC) class II in resting B cells was not enhanced in response to IL-4. IL-4 induced B-cell proliferation costimulated by anti-IgM antibody was abolished. The T-cell proliferative response was also notably reduced. Furthermore, production of Th2 cytokines from T cells as well as IgE and IgG1 responses after nematode infection were profoundly reduced. These findings agreed with those obtained in IL-4 deficient mice or using antibodies to IL-4 and the IL-4 receptor. We conclude that Stat6 plays a central role in exerting IL-4 mediated biological responses.
1,526 citations
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