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In vivo splenic CD11c cells downregulate CD4 T-cell response thereby decreasing systemic immunity to gene-modified tumour cell vaccine

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Abstract

One of the factors influencing the efficacy of tumour cell vaccines is the site of immunization. We have shown previously that gene-modified vaccines delivered directly inside the spleen induced antigen cross-presentation by splenic antigen-presenting cells (not B cells). Here, we examined the interaction between splenic CD11c+ cells and antigen-specific CD4+ T cells. We used tumour cells expressing ovalbumin (OVA), a situation where CD4+ T-cell help is required for the generation of a cytotoxic T lymphocyte response. Using in vivo bioluminescence imaging of luciferase-expressing EL4-OVA cells, we could demonstrate that tumour cells were located exclusively inside the spleen following intrasplenic injection. We showed that after intrasplenic immunization with T/SA-OVA cells, splenic class I+ class II+ CD11c+ cells engulfed and presented in vivo the OVA class I-restricted peptide SIINFEKL. However, in vivo previously adoptively transferred 5,6-carboxy-succinimidyl-fluorescein-ester-labelled transgenic CD4+KJI-26+ cells specific for the class II OVA323–339 peptide underwent abortive proliferation in the spleen. These CD4+KJI-26+ cells were only transiently activated and produced IL-10 and IL-4 and not IFN-γ. It appears that splenic CD11c+ cells can downregulate splenic specific CD4+ T-cell response thereby leading to a decrease in antitumour systemic immunity.

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Acknowledgements

We thank Andrea Katzer and Ute Nitschke for excellent technical assistance. This work was supported by Grant 2001.106.1 from the Wilhelm-Sander-Stiftung and by the Deutsche Forschungsgemeinschaft (Transregio-Sonderforschungsprogramm 36 Projekt B2).

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Authors and Affiliations

  1. Charité-am-MDC, Campus Buch, Berlin, Germany

    S Cayeux, B Bukarica, M Bunse & B Dörken

  2. Max-Delbrück-Center for Molecular Medicine, Berlin, Germany

    C Buschow, J Charo & T Blankenstein

  3. Charité, Campus Benjamin Franklin, Institute for Immunology, Berlin, Germany

    T Blankenstein

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  1. S Cayeux
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  2. B Bukarica
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  3. C Buschow
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  4. J Charo
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  5. M Bunse
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  6. B Dörken
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  7. T Blankenstein
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Correspondence to S Cayeux.

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Cayeux, S., Bukarica, B., Buschow, C. et al. In vivo splenic CD11c cells downregulate CD4 T-cell response thereby decreasing systemic immunity to gene-modified tumour cell vaccine. Gene Ther 14, 1481–1491 (2007). https://doi.org/10.1038/sj.gt.3303003

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