IL-4 Regulates Bim Expression and Promotes B Cell Maturation in Synergy with BAFF Conferring Resistance to Cell Death at Negative Selection Checkpoints

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 (B220lowIgMlowCD23−) and transitional (B220intIgMhighCD23−) 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.

γδ T cells affect IL-4 production and B-cell tolerance

“…More recently, it was found that IL-4 produces Fas resistance in B cells and a breakdown of B-cell tolerance in vivo with autoantibody formation, proteinuria, and tissue damage (44). Moreover, it was shown that IL-4 regulates Bim expression, promotes B-cell maturation in synergy with B-cell activating factor, and confers resistance to B-cell death at negative selection checkpoints (45). In IL-4 transgenic mice, constitutive expression of this cytokine causes autoimmune-type disorders (32).…”

Transitional B cells involved in autoimmunity and their impact on neuroimmunological diseases

“…IL-4 stimulates the development of CD23 − TrB cells into CD23 + TrB cells, an effect comparable to that driven by BAFF [77]. However, IL-4 was found to render bone marrow TrB cells refractory to anti-IgM apoptotic signals, which was distinct from BAFF [77]. Thus, IL-4 and stromal cells play major roles in improving the survival of human T1 B cells and promoting their maturation [5].…”

“…IL-4 is a multifunctional cytokine that promotes mature B cell activation and induces B cell differentiation, proliferation, and antibody secretion by acting as a cofactor for lipopolysaccharides, CD40L, and antigen stimulation [77,78]. IL-4 stimulates the development of CD23 − TrB cells into CD23 + TrB cells, an effect comparable to that driven by BAFF [77]. However, IL-4 was found to render bone marrow TrB cells refractory to anti-IgM apoptotic signals, which was distinct from BAFF [77].…”

Revisiting the Interaction of γδ T-Cells and B-Cells

“…The presence of these autoantibodies is probably explained by the ability of the remaining Vγ1 + T-cells and, mainly, αβ T-cells (regulated by the γδ T-cells) for producing large amounts of IL-4 that activate B-cell maturation and can overrun tolerance mechanisms [13,15,47]. IL-4 production may be implicated in the breakdown of B-cell tolerance by promoting the survival of BCR-mediated apoptosis of splenic B-cells and transitional B-cells during negative selection [88][89][90]. In addition, Tcrb −/− mice were able to generate self-reactive antibodies after parasitic infection, in particular towards DNA instead of antibodies specific for the pathogen, thereby supporting the idea that γδ T-cells are more important for autoantibody production rather than mounting a pathogen-specific immune reaction [79].…”