IL-4 induces characteristic Th2 responses even in the combined absence of IL-5, IL-9, and IL-13

Functional redundancy is highly prevalent among the Th2 interleukins (IL)-4, IL-5, IL-9, and IL-13. To define the critical functions of these cytokines, we have generated a novel panel of compound Th2 cytokine-deficient mice (from single to quadruple cytokine knockouts). We find that these Th2 cytokines are not essential for fetal survival even during allogeneic pregnancy. Using intestinal parasite infection and a pulmonary granuloma model, we demonstrate cryptic roles for IL-4, IL-5, IL-9, and IL-13 in these responses. Significantly, although IL-5, IL-9, and IL-13 add to the speed and magnitude of the response, a threshold is reached at which IL-4 alone can activate all Th2 effector functions. These mice reveal distinct spatial, temporal, and hierarchical cytokine requirements in immune function.