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Interleukin-4 impairs granzyme-mediated cytotoxicity of Simian virus 40 large tumor antigen-specific CTL in BALB/c mice

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Abstract

In this report we analyzed the impact of interleukin-4 (IL-4) on tumor-associated simian virus 40 (SV40) large T-antigen (TAg)-specific CD8+ cytotoxic T cells during rejection of syngeneic SV40 transformed mKSA tumor cells in BALB/c mice. Strikingly, challenge of naïve mice with low doses of mKSA tumor cells revealed a CD8+ T cell-dependent prolonged survival time of naïve IL-4−/− mice. In mice immunized with SV40 TAg we observed in IL-4−/− mice, or in wild type mice treated with neutralizing anti-IL-4 monoclonal antibody, a strongly enhanced TAg-specific cytotoxicity of tumor associated CD8+ T cells. The enhanced cytotoxicity in IL-4−/− mice was accompanied by a significant increase in the fraction of CD8+ tumor associated T-cells expressing the cytotoxic effector molecules granzyme A and B and in granzyme B-specific enzymatic activity. The data suggest that endogenous IL-4 can suppress the generation of CD8+ CTL expressing cytotoxic effector molecules especially when the antigen induces only a very weak CTL response.

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Abbreviations

TAg:

SV40 large tumor antigen

TAL:

Tumor associated lymphocytes

CTL:

Cytotoxic T lymphocytes

IL-4:

Interleukin-4

gzm:

Granzyme

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Acknowledgments

This work was supported by Research Grant Le 132/29-1 from the Deutsche Forschungsgemeinschaft, Research Grant 93.048.2 from the Wilhelm Sander-Stiftung and the Fond der Chemischen Industrie. The Heinrich-Pette-Institut is financially supported by the Freie und Hansestadt Hamburg and the Bundesminsiterium für Gesundheit und Soziale Sicherung. We are grateful to Markus M. Simon, who kindly provided granzyme A-specific antiserum.

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Author notes

  1. Roland Gugel

    Present address: PolyGene AG, 8153, Rümlang, Switzerland

  2. Daniela Paulsen

    Present address: AiCuris GmbH & Co. KG, Aprather Weg 18a / Geb. 405, 42113, Wuppertal, Germany

Authors and Affiliations

  1. Institute for Medical Microbiology, Immunology und Hygiene, Medical Center of the University of Cologne, 50935, Cologne, Germany

    Nikola Baschuk, Olaf Utermöhlen, Ulrike Karow & Martin Krönke

  2. Heinrich-Pette-Institute for Experimental Virology and Immunology, University of Hamburg, 20251, Hamburg, Germany

    Roland Gugel, Gabriele Warnecke, Daniela Paulsen & Wolfgang Deppert

  3. Institute for Infectious Diseases and Molecular Medicine (IIDMM), University of Cape Town, 7925, Cape Town, South Africa

    Frank Brombacher

  4. Center for Molecular Medicine, University of Cologne, 50935, Cologne, Germany

    Martin Krönke

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  1. Nikola Baschuk
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Correspondence to Olaf Utermöhlen.

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Nikola Baschuk and Olaf Utermöhlen contributed equally to this work.

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Baschuk, N., Utermöhlen, O., Gugel, R. et al. Interleukin-4 impairs granzyme-mediated cytotoxicity of Simian virus 40 large tumor antigen-specific CTL in BALB/c mice. Cancer Immunol Immunother 56, 1625–1636 (2007). https://doi.org/10.1007/s00262-007-0309-0

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