094 IFN-gamma-mediated inhibition of human IgE synthesis by IL-21 is associated with a polymorphism in the IL-21 R gene

Introduction IL-21 is a cytokine produced by CD4+ T cells that has been reported to regulate human, as well as, mouse T and NK cell function and to inhibit antigen-induced IgE production by mouse B cells. Methods Human splenic or peripheral B cells were activated in vitro with an anti-CD40 monoclonal antibody (mAb) and IL-4, in the presence or absence of IL-21, and the production of IgE, as well as the expression of IL-4-induced germline epsilon trans-cripts by these cells were analyzed by isotype-specific ELISA and Northern blotting analysis, respectively. The polymorphism of the IL-21R gene was determined by DNA sequencing analysis. Results Although rIL-21 does not affect rIL-4-induced germline epsilon mRNA expression in purified human spleen or peripheral blood B cells, it strongly enhances IgE production by both CD 19+, CD27- naive, and CD19+.CD27+ memory B cells, stimulated with anti-CD40 mAb and rIL-4. However, rIL-21 inhibits allergen-induced IgE production in peripheral blood mononuclear cells (PBMC), as well as rIL-4-induced production of this isotype in cultures of PBMC or total splenocytes, by an IFN- gamma-dependent mechanism. The presence of a polymorphism (T-83C), encoding a variant IL-21R, in donors heterozygous for this mutation was not only associated with a lower sensitivity to the IgE production inhibiting effects rIL-21, but also with lower rIL-21-induced IFN-gamma production levels, as compared to donors carriyng the wild-type allele of the IL-21R. Conclusion These results show that IL-21 differentially regulâtes IL-4-induced human IgE production, via its growth-promoting capacity on IgE-committed B cells, as well as via its ability to induce the production of IFN-gamma, most likely by T and NK cells, whereas the outcome of these IL-21-mediated effects is dependent on the presence of a polymorphism in the IL-21R.