The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1999/3/803/ $5.00
The Journal of Experimental Medicine, Volume 189, Number 5, March 1, 1999 803-810

Articles

T Helper Cell Type 1–associated and Cytotoxic T Lymphocyte–mediated Tumor Immunity Is Impaired in Interleukin 4–deficient Mice

Thomas Schüler*, Zhihai Qin*, Sabrina Ibe*, Nancy Noben-Trauth{ddagger}, and Thomas Blankenstein*

From the * Max-Delbrück-Center for Molecular Medicine, 13122 Berlin, Germany; and the {ddagger} Laboratory of Immunology, National Institutes of Health, Rockville, Maryland 20582

It is widely accepted that cellular immune responses are induced by CD4+ T helper 1 (Th1) cells secreting interleukin (IL)-2 and interferon (IFN)-{gamma}. 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-{gamma} 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.

Key Words: tumor vaccination • interleukin 4 • T cell immunity • interleukin 4–deficient mice

Address correspondence to Thomas Schüler, Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Str. 10, 13122 Berlin, Germany. Phone: 49-30-9406-2687; Fax: 49-30-9406-2453; E-mail: tschue{at}mdc-berlin.de


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