Retrovirally transduced mouse dendritic cells require CD4(+) T cell help to elicit antitumor immunity: Implications for the clinical use of dendriticcells

Presentation of MHC class I-restricted peptides by dendritic cells (DCs) ca n elicit vigorous antigen-specific CTL responses in vivo. It is well establ ished, however, that T cell help can augment CTL function, raising the ques tion of how best to present tumor-associated MHC class I epitopes to induce effective tumor immunity. To this end, we have examined the role of MHC cl ass II peptide-complexes present on the immunizing DCs in a murine melanoma model. To present MHC class I- and II-restricted Ags reliably on the same cell, we retrovirally transduced bone marrow-derived DCs with the model Ag OVA encoding well-defined class I- and II-restricted epitopes, The importan ce of CD4(+) T cells activated by the immunizing DCs in this model is demon strated by the following findings: 1) transduced DCs presenting class I and class II epitopes are more efficient than class I peptide-pulsed DCs; 2) M HC class II-deficient DCs fail to induce tumor protection; 3) CD4(+) T cell depletion abolishes induction of tumor protection; and 4) DCs presenting b ovine serum Ags are more effective in establishing tumor immunity than DCs cultured in syngeneic serum. When MHC class II-deficient DCs were directly activated via their CD40 receptor, we indeed observed a moderate elevation of OVA-specific CTL activity. However, this increase in CTL activity was no t sufficient to induce in vivo tumor rejection. Thus, our results demonstra te the potency of genetically modified DCs that express both MHC class I an d II epitopes, but caution against the use of DCs presenting only the forme r.