IL-4 regulates Bim expression and promotes B cell maturation in synergy with BAFF conferring resistance to cell death at negative selection checkpoints.
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.
Department of Immunology, Institute of Microbiology, Federal University of Rio de Janeiro, Rio de Janeiro 21941-590, Brazil.
Alessandra
A
Granato
Department of Immunology, Institute of Microbiology, Federal University of Rio de Janeiro, Rio de Janeiro 21941-590, Brazil.
Elize A
EA
Hayashi
Department of Immunology, Institute of Microbiology, Federal University of Rio de Janeiro, Rio de Janeiro 21941-590, Brazil.
Barbara J A
BJ
Baptista
Department of Immunology, Institute of Microbiology, Federal University of Rio de Janeiro, Rio de Janeiro 21941-590, Brazil.
Maria
M
Bellio
Department of Immunology, Institute of Microbiology, Federal University of Rio de Janeiro, Rio de Janeiro 21941-590, Brazil afnobrega@gmail.com.
Alberto
A
Nobrega
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000276:immunology*; D015551:Autoimmunity / Q000502:physiology; D053264:B-Cell Activating Factor / Q000235:genetics / Q000276:immunology*; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology*; D000072224:Bcl-2-Like Protein 11; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology*; D007075:Immunoglobulin M / Q000235:genetics / Q000276:immunology; D015847:Interleukin-4 / Q000235:genetics / Q000276:immunology*; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000276:immunology*; D011947:Receptors, Antigen, B-Cell / Q000235:genetics / Q000276:immunology; D017455:Receptors, IgE / Q000235:genetics / Q000276:immunology
D051017:Apoptosis Regulatory Proteins; D053264:B-Cell Activating Factor; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D007075:Immunoglobulin M; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D011947:Receptors, Antigen, B-Cell; D017455:Receptors, IgE; C505720:Tnfsf13b protein, mouse; D015847:Interleukin-4