The IgM receptor FcμR limits tonic BCR signaling by regulating expression of the IgM BCR

Nguyen, Trang; Kläsener, Kathrin; Zürn, Christa; Castillo, Patricia; Brust‐Mascher, Ingrid; Imai, Denise M.; Bevins, Charles L.; Reardon, Colin; Reth, Michael; Baumgarth, Nicole

doi:10.1038/ni.3677

Cited by 72 publications

(139 citation statements)

References 51 publications

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“…Heterozygous μs +/− mice were created by intercrossing μs −/− and C57BL/6J mice. Fcmr flx/flx mice were generated by the UC Davis Mouse Biology Program MBP) using ES cells with a targeted deletion of exon 4 of the FcμR, generated by the UC Davis MBP (32). Fcmr flx/flx mice were bred with global Cre-expressing ( Cmv -Cre) mice to generate total knock out mice ( Fcmr −/− ), which let to the removal of the FcmR in germline.…”

Section: Methodsmentioning

confidence: 99%

“…C57BL/6 (WT) mice from Jackson were used as controls. Fcmr flx/flx mice were also bred with Cd19 -Cre + mice to generate Fcmr flx/flx Cd19 -Cre + mice with a B cell-specific deletion of the FcμR as described (32). Cre negative littermates served as controls.…”

Section: Methodsmentioning

confidence: 99%

“…Total RNA from different B cell subsets was isolated as previously described (32). Fcmr mRNA expression was measured using a commercial primer/probe set (Mm01302388_m1; Applied Biosystems).…”

Section: Methodsmentioning

confidence: 99%

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sIgM–FcμR Interactions Regulate Early B Cell Activation and Plasma Cell Development after Influenza Virus Infection

Nguyen

Graf

Randall

et al. 2017

The Journal of Immunology

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Previous studies with mice lacking secreted IgM (sIgM) due to a deletion of the μs splice region (μs−/−) had shown sIgM involvement in normal B cell development and in support of maximal antigen-specific IgG responses. Because of the changes to B cell development, it remains unclear to which extent and how sIgM directly affects B cell responses. Here we aimed to explore the underlying mechanisms of sIgM-mediated IgG response regulation during influenza virus infection. Generating mice with normally developed μs-deficient B cells we demonstrate that sIgM supports IgG responses by enhancing early antigen-specific B cell expansion, not by altering B cell development. Lack of FcμR expression on B cells, but not lack of Fcα/μR expression or complement activation, reduced antiviral IgG responses to the same extent as observed in μs−/− mice. B-cell-specific Fcmr−/− mice lacked robust clonal expansion of influenza hemagglutinin-specific B cells early after infection and developed fewer spleen and bone marrow IgG plasma cells and memory B cells, compared to controls. However, germinal center responses appeared unaffected. Provision of sIgM rescued plasma cell development from μs−/− but not Fcmr−/− B cells, as demonstrated with mixed bone marrow chimeric mice. Together the data suggest that sIgM interacts with FcμR on B cells to support early B cell activation and the development of long-lived humoral immunity.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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sIgM–FcμR Interactions Regulate Early B Cell Activation and Plasma Cell Development after Influenza Virus Infection

Nguyen

Graf

Randall

et al. 2017

The Journal of Immunology

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“…Conclusions from the earlier studies that reported expansion of B-1a cell populations in the absence of sIgM (67, 68) were thus likely based on the somewhat subtle phenotypic differences between B-1a cells and anergic B cells. B-1 cell frequencies were either unaffected or even enhanced in mice that lacked the FcμR (72–74), although FcμR −/− mice had increased B-1 cell-derived serum IgM-levels. Therefore, sIgM does not appear to provide a direct negative feedback signal for B-1 cell development and/or expansion.…”

Section: B-1 Cell Repertoire Selection and Maintenancementioning

confidence: 99%

“…This is supported by studies with gene-targeted mice that show enhanced BCR signaling and increased serum IgM levels in mice with deletions of a repressor of BCR-signaling, such as the two members of the sialic acid-binding immunoglobulin (Ig)-like lectin family, CD22 and Siglec G (75), as well as CD72 (13). Furthermore, B cell specific deletion of the FcμR, which was shown to increase BCR expression and BCR tonic signaling due to enhanced BCR transport from the trans-Golgi (72), resulted in increased numbers of CD138+ B-1 plasma cells in the spleen and higher concentrations of serum IgM (72). In all cases, however, both B-1 cell development and B-1 cell differentiation were enhanced.…”

Section: B-1 Cell Regulation and Functionsmentioning

confidence: 99%

A Hard(y) Look at B-1 Cell Development and Function

Baumgarth

2017

The Journal of Immunology

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105

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A small population of B cells exists in lymphoid tissues and body cavities of mice that is distinct in development, phenotype and function from the majority (B-2) B cell population. This population, originally termed “Ly1” and now “B-1”, has received renewed interest as an innate-like B cell population of fetal-derived hematopoiesis, responsible for natural antibody production and rapid immune responses. Molecular analyses have begun to define fetal and adult hematopoiesis, while cell-fate mapping studies have revealed complex developmental origins of B-1 cells. Together the studies provide a more detailed understanding of B-1 cell regulation and function. This review outlines studies that defined B-1 cells as natural antibody and cytokine-producing B cells of fetal origin, with a focus on work conducted by Randy Hardy, an early pioneer and co-discoverer of B-1 cells, whose seminal contributions enhanced our understand of this enigmatic B cell population.

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Enhanced Mott cell formation linked with IgM Fc receptor (FcμR) deficiency

et al. 2023

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In previous studies, Mott cells, an unusual form of plasma cells containingIg-inclusion bodies, were frequently observed in peripheral lymphoid tissues in our IgM Fc receptor (FcμR)-deficient (KO) mouse strain. Because of discrepancies in the reported phenotypes of different Fcmr KO mouse strains, we here examined two additional available mutant strains and confirmed that such enhanced Mott-cell formation was a general phenomenon associated with FcμR deficiency. Splenic B cells from Fcmr KO mice clearly generated more Mott cells than those from WT mice when stimulated in vitro with LPS alone or a B-1, but not B-2, activation cocktail. Nucleotide sequence analysis of the Ig variable regions of a single IgMλ + Mott-hybridoma clone developed from splenic B-1 B cells of Fcmr KO mice revealed the near (VH) or complete (Vλ) identity with the corresponding germline gene segments and the addition of six or five nucleotides at the VH/DH and DH/JH junctions, respectively. Transduction of an FcμR cDNA into the Mott hybridoma significantly reduced cells containing IgM-inclusion bodies with a concomitant increase in IgM secretion, leading to secreted IgM binding to FcμR expressed on Mott transductants. These findings suggest a regulatory role of FcμR in the formation of Mott cells and IgM-inclusion bodies.

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The IgM receptor FcμR limits tonic BCR signaling by regulating expression of the IgM BCR

Cited by 72 publications

References 51 publications

sIgM–FcμR Interactions Regulate Early B Cell Activation and Plasma Cell Development after Influenza Virus Infection

sIgM–FcμR Interactions Regulate Early B Cell Activation and Plasma Cell Development after Influenza Virus Infection

A Hard(y) Look at B-1 Cell Development and Function

Enhanced Mott cell formation linked with IgM Fc receptor (FcμR) deficiency

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