Simultaneous disruption of interleukin (IL)-4 and IL-13 defines individualroles in T helper cell type 2-mediated responses

Using a single vector targeting strategy, we have generated mice with a com bined deficiency of interleukin (IL)-4 and IL-13 to clarify their roles in T helper type 2 (Th2) cell responses. Using immunological challenges normal ly characterized by a Th2-like response, we have compared the responses of the double-deficient mice with those generated by wild-type, IL-4-deficient , and IL-13-deficient mice. Using a pulmonary granuloma model, induced with Schistosoma mansoni eggs, we demonstrate that although eosinophil infiltra tion, immunoglobulin E, and IL-5 production are reduced in the IL-4-deficie nt mice and IL-13-deficient mice, they are abolished only in the combined a bsence of both cytokines. Furthermore, IL-4/13-deficient animals are severe ly impaired in their ability to expel the gastrointestinal nematode Nippost rongylus brasiliensis. Unexpectedly, N. brasiliensis-infected IL-4/13-defic ient mice developed elevated IL-5 and eosinophilia, indicating that compens atory mechanisms exist for the expression of IL-5, although serum IgE remai ned undetectable. IL-4/13-deficient mice default to a Th1-like phenotype ch aracterized by the expression of interferon gamma and the production of IgG 2a and IgG2b. We conclude that IL-4 and IL-13 cooperate to initiate rapid T h2 cell-driven responses, and that although their functions overlap, they p erform additive roles.