Late IL‐3–induced phenotypic and functional alterations in human basophils require continuous IL‐3 receptor signaling

Cytokines of the GM‐CSF family signal via the same receptor subunit (βc) and, thus, have overlapping effects on cells that express all cytokine‐specific α‐chains (IL‐3Rα, IL‐5Rα, GM‐CSFRα), such as human basophils, whose rapid effector functions are similarly enhanced by IL‐3, IL‐5, and GM‐CSF. However, previous work has shown that IL‐3, but not IL‐5 and GM‐CSF, supports and induces allergy‐associated functions of human basophils at later time points. This includes induction of Th2 cytokine and chemokine secretion, high‐affinity IgE receptor–independent leukotriene C4 (LTC4) formation, expression of enzymes (e.g., RALDH2, granzyme B), and kinases (e.g., Pim1). Here, we address the question of why IL‐3, but not IL‐5 or GM‐CSF, is capable of inducing these late responses in human basophils, and we investigate the mechanism that underlies the unique regulatory capacity of IL‐3. We find that IL‐3, IL‐5, and GM‐CSF rapidly activate the same canonical signaling cascades in a qualitatively identical manner with comparable strength, but we identify signaling duration as major discriminating factor. IL‐5 and GM‐CSF rapidly down‐regulate surface levels of their receptors within minutes, concomitant with a rapid decay in signaling molecule activation and time‐dependent loss of ability of these cytokines to prime basophils for functional responses. By contrast, IL‐3 hardly down‐regulates the α‐chain of its receptor without depleting the common β‐chain, which enables extraordinarily sustained signaling events, predominantly the activation of Stat5. Of interest, acute IL‐3 signaling is not sufficient to induce persistent phenotypical and functional changes in human basophils. Induction of these functional late responses depends on continuous IL‐3 receptor activation and signaling.