T helper cell type 1-associated and cytotoxic T lymphocyte-mediated tumor immunity is impaired in interleukin 4-deficient mice

It is widely accepted that cellular immune responses are induced by CD4(+) T helper 1 (Th1) cells secreting interleukin (IL)-2 and interferon (IFN)-ga mma. Tumor immunity is often mediated by cytotoxic T lymphocytes (CTLs) who se activation is supported by Th1 cytokines. Since IL-4 directs Th2 develop ment and has been shown to inhibit Th1-dominated responses, we assumed that IL-4-deficient (IL-4(-/-)) mice would develop vigorous CTL-mediated tumor immunity compared with IL-4-competent (IL-4(+/+)) mice. Surprisingly, IL-4( -/-) mice were severely impaired to develop tumor immunity to both a mammar y adenocarcinoma line and a colon carcinoma line. The lack of tumor immunit y in IL-4(-/-) mice was associated with reduced IFN-gamma production, dimin ished levels of tumor-reactive serum IgG2a, and undetectable CTL activity, indicating a defective Th1 response in the absence of endogenous IL-4. Anti -IL-4 monoclonal antibody blocked tumor immunity in IL-4(+/+) mice when adm inistered at the time of immunization but not at the time of challenge. Add itionally, tumor immunity could be induced in IL-4(-/-) mice, if IL-4 was p rovided by gene-modified cells together with immunizing tumor cells. These results demonstrate that tumor immunity requires IL-4 in the priming phase for the generation of effector calls rather than for their maintenance and exclude secondary, developmental defects in the "knockout" strain. Together , our results demonstrate a novel and previously unanticipated role of IL-4 for the generation of Th1-associated, CTL-mediated tumor immunity.