Among other molecular determinants, Interleukin-21 (IL-21) emerges as a significant player in modulating IgE responses. IL-21, a cytokine belonging to the type I cytokine family, is known for its broad immunomodulatory effects impacting a variety of immune cells including T, B, and natural killer cells. IL-21 is predominantly produced by CD4+ T cells, particularly T follicular helper (Tfh) cells, and exerts a significant influence on the immune response. Its receptor, IL-21R, is expressed on various immune cells, allowing IL-21 to modulate growth, differentiation, and function. The relationship between IL-21 and IgE production has been a subject of considerable interest. Studies have shown that IL-21 can modulate IgE synthesis in various ways. Hiromura et al. (2007) demonstrated that administration of IL-21 in a murine model of allergic rhinitis significantly reduced symptoms and serum concentrations of ovalbumin (OVA)-specific IgE, indicating a suppressive effect of IL-21 on IgE synthesis. This was a pivotal finding, linking IL-21 directly to the suppression of IgE [
36]. Further, Jen et al. (2015) showed that IL-21 inhibits IgE secretion from B cells stimulated by the combination of CD40 ligand and IL-4. This negative regulatory role of IL-21 in IgE production suggests its potential utility in therapeutic interventions for allergic diseases [
37]. The modulation of B cell function by IL-21 is a critical factor in its regulation of IgE levels. B cells undergo class switch recombination (CSR) to produce IgE, and IL-21 directly influences this process (
Fig. 1). Kishida et al. (2007) found that treatment with IL-21 in anaphylactic mice models suppressed IgE CSR in splenic B cells, resulting in a significant decrease in serum concentrations of both total and allergen-specific IgE. These findings underscore the importance of IL-21 in regulating B cell function and, consequently, IgE production in allergic responses [
38]. Additionally, the interplay between IL-21 and T cells is significant in the context of allergic diseases. IL-21 influences the differentiation and function of Tfh cells, which are integral to B cell activation and subsequent IgE production. Fröhlich et al. (2007) highlighted the role of IL-21R signaling in Th2 immune responses. Given that Th2 responses are closely associated with allergic reactions and IgE production, this finding suggests that IL-21's action on T cells has an indirect yet significant impact on IgE regulation in allergic responses [
39].