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J Immunol ; 192(12): 5761-75, 2014 Jun 15.
Article in English | MEDLINE | ID: mdl-24835393

ABSTRACT

IL-4 plays an essential role in the activation of mature B cells, but less is known about the role of IL-4 in B cell maturation and tolerance checkpoints. In this study, we analyzed the effect of IL-4 on in vitro B cell maturation, from immature to transitional stages, and its influence on BCR-mediated negative selection. Starting either from purified CD19(+)IgM(-) B cell precursors, or sorted bone marrow immature (B220(low)IgM(low)CD23(-)) and transitional (B220(int)IgM(high)CD23(-)) B cells from C57BL/6 mice, we compared the maturation effects of IL-4 and BAFF. We found that IL-4 stimulated the generation of CD23(+) transitional B cells from CD23(-) B cells, and this effect was comparable to BAFF. IL-4 showed a unique protective effect against anti-IgM apoptotic signals on transitional B cell checkpoint, not observed with BAFF. IL-4 and BAFF strongly synergized to promote B cell maturation, and IL-4 also rendered it refractory to BCR-mediated cell death. IL-4 blocked upregulation of proapoptotic Bim protein levels induced by BCR crosslinking, suggesting that diminished levels of intracellular Bim promote protection to BCR-induced cell death. Evidence was obtained indicating that downmodulation of Bim by IL-4 occurred in a posttranscriptional manner. Consistent with data obtained in vitro, IL-4 in vivo was able to inhibit Bim upregulation and prevent cell death. These results contribute to the understanding of the role of IL-4 in B lymphocyte physiology, unveiling a previously undescribed activity of this cytokine on the maturation of B cells, which could have important implications on the breaking of B cell central tolerance in autoimmunity.


Subject(s)
Apoptosis Regulatory Proteins/immunology , Apoptosis/immunology , B-Cell Activating Factor/immunology , B-Lymphocytes/immunology , Gene Expression Regulation/immunology , Interleukin-4/immunology , Membrane Proteins/immunology , Proto-Oncogene Proteins/immunology , Animals , Apoptosis/genetics , Apoptosis Regulatory Proteins/genetics , Autoimmunity/physiology , B-Cell Activating Factor/genetics , B-Lymphocytes/cytology , Bcl-2-Like Protein 11 , Gene Expression Regulation/genetics , Immunoglobulin M/genetics , Immunoglobulin M/immunology , Interleukin-4/genetics , Membrane Proteins/genetics , Mice , Mice, Inbred BALB C , Proto-Oncogene Proteins/genetics , Receptors, Antigen, B-Cell/genetics , Receptors, Antigen, B-Cell/immunology , Receptors, IgE/genetics , Receptors, IgE/immunology
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