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 OVA 323-339 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-g. It appears that splenic CD11c + cells can downregulate splenic specific CD4 + T-cell response thereby leading to a decrease in antitumour systemic immunity.