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J. Exp. Med.,
Volume 189, Number 5, March 1, 1999 803-810
By
From the * Max-Delbrück-Center for Molecular Medicine, 13122 Berlin, Germany; and the It is widely accepted that cellular immune responses are induced by CD4+ T helper 1 (Th1)
cells secreting interleukin (IL)-2 and interferon (IFN)- Laboratory of Immunology, National Institutes of Health, Rockville, Maryland 20582
. Tumor immunity is often mediated
by cytotoxic T lymphocytes (CTLs) whose activation is supported by Th1 cytokines. Since IL-4 directs Th2 development 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 mammary adenocarcinoma line and a
colon carcinoma line. The lack of tumor immunity in IL-4/ mice was associated with reduced IFN- production, diminished 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 administered at the time
of immunization but not at the time of challenge. Additionally, tumor immunity could be induced in IL-4/ mice, if IL-4 was provided 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 cells 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.
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