Notch-RBP-J-Independent Marginal Zone B Cell Development in IgH Transgenic Mice with VH Derived from a Natural Polyreactive Antibody

Zhuo Zhang,Ying Xing,Hua Han,Xinbin Hu,Yaochun Wang,Yufeng Liu,Lihong Hou,Lanhua Zhou,Ping Zhang,Wei Li,Xinwei Yang,Antonio A Freitas

doi:10.1371/journal.pone.0038894

Zhuo Zhang, Ying Xing + Show 10 more

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https://doi.org/10.1371/journal.pone.0038894

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Journal: PLoS ONE	Publication Date: Jun 13, 2012
Citations: 29	License type: CC BY 4.0

Affiliation: Air Force Medical University, Xijing Hospital

Abstract

Both the B cell antigen receptor (BCR) signaling and Notch signaling pathway play important roles in marginal zone (MZ) B cell development; however, if and how these two signaling pathways engage in crosstalk with each other remain unclear. In the present study, IgH transgenic mice (TgVH3B4) were crossed with mice with Notch downstream transcription factor RBP-J floxed alleles (RBP-Jf/f) and Mx-Cre transgene. Subsequently, MZ B cell development was analyzed in 3B4/Cre/RBP-Jf/f mice that expressed the transgenic 3B4 IgH and exhibited a deficiency in Notch signaling in B cells upon poly (I:C) injection. We observed that MZ B cell numbers were severely reduced, but still detectable in 3B4/Cre/RBP-Jf/f mice, in contrast to increased numbers of MZ B cells in TgVH3B4 mice and almost no MZ B cells in Cre/RBP-Jf/f mice. The majority of the MZ B cells in the 3B4/Cre/RBP-Jf/f mice had the same antigen specificity with that of 3B4 antibody, indicating that a particular BCR specificity might direct MZ B cell development in the absence of Notch signaling. The number of MZ B precursor (MZP) cells was reduced sharply in 3B4/Cre/RBP-Jf/f mice, and the number of transitional stage 1 and transitional stage 2 cells did not change that much, indicating that the interaction between BCR and Notch signaling likely occurred during the T2-MZP stage. Based on the transgenic mouse model, our data indicate that MZ B cells with certain BCR specificity can develop in a Notch-RBP-J independent manner.

Highlights

Marginal zone (MZ) B cells are a separate B cell lineage distinct from mature follicular (FO) B cells and B-1 cells, and are critical determinants of the host defense against blood-borne bacterial pathogens [1,2]
Abrogation of Notch signaling attenuated MZ B cell development in IgH transgenic mice To induce the deletional inactivation of RBP-J through Cre expression in the IgH transgenic mice TgVH3B4, mice containing the floxed RBP-J allele were bred with TgVH3B4 mice and MxCre transgenic mice in which Cre recombinase expression is transactivated by the Mx promoter after the IFN-a inducer ploy (I:C) injection [37]
The population of MZ B cells in the 3B4/Cre/RBP-Jf/f mice was greatly reduced compared with the 3B4/Cre/RBP-Jf/+ mice; the proportion of MZ B cells in 3B4/Cre/RBP-Jf/f mice was still much higher compared with the Cre/RBP-Jf/f mice (Figure 1)

Summary

Introduction

Marginal zone (MZ) B cells are a separate B cell lineage distinct from mature follicular (FO) B cells and B-1 cells, and are critical determinants of the host defense against blood-borne bacterial pathogens [1,2]. Pre-B cells undergo a second round of BCR rearrangement at the VL loci to generate immature B cells that possess a functional BCR [9]. These immature B cells undergo negative selection, during which B cell clones that respond to self-antigens are cleared through apoptosis, anergy, or receptor editing [10,11,12]. These cells acquire surface IgD and CD23 expression while maintaining the expression of markers of immaturity These cells are considered transitional stage 2 (T2) B cells [13,14]. T2 B cells differentiate directly into FO B cells or pass through the T2-MZ B cell progenitor (MZP) stage into the MZ B cell compartment [2]

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