Model of cytokine-mediated regulation of IgE production: role of STAT3. (A) Under normal conditions, CD4⁺ T (and NK T) cells produce IL-4, IL-21, IL-10, and IFN-γ (among other cytokines) in response to stimulation through the TcR. Production of IFN-γ^32-34  and IL-10 (Figure 5) can be enhanced by IL-21. IL-4, and IL-21 alone can induce IgE secretion by naive B cells; however, they act synergistically in a STAT3-dependent manner to promote secretion of high levels of IgE. Induction of IgE by IL-4 is negatively regulated by IL-10 and IFN-γ; the net result of the interplay between IL-4, IL-21, IL-10, and IFN-γ is production of a low basal level of IgE. (B) In HIES because of mutations in STAT3, the ability of (for example) IL-21 to heighten IL-10 and IFN-γ production by activated CD4⁺ T (and NKT) cells is abrogated; consequently, the suppressive effects of these cytokines on IgE production are attenuated. This is further compounded by the inability of HIES B cells to respond to the regulatory effects of IL-10, which acts through STAT3. Thus, despite the B cells being unable to respond to IL-21, their responses to the stimulatory effects of IL-4 are dysregulated, resulting in excessive production of IgE, a hallmark of HIES.