Retrovirally transduced mouse dendritic cells require CD4+ T cell help to elicit antitumor immunity: implications for the clinical use of dendritic cells.
Presentation of MHC class I-restricted peptides by dendritic cells (DCs) can elicit vigorous antigen-specific CTL responses in vivo. It is well established, however, that T cell help can augment CTL function, raising the question 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 class 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 importance of CD4+ T cells activated by the immunizing DCs in this model is demonstrated by the following findings: 1) transduced DCs presenting class I and class II epitopes are more efficient than class I peptide-pulsed DCs; 2) MHC class II-deficient DCs fail to induce tumor protection; 3) CD4+ T cell depletion abolishes induction of tumor protection; and 4) DCs presenting bovine 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 not sufficient to induce in vivo tumor rejection. Thus, our results demonstrate the potency of genetically modified DCs that express both MHC class I and II epitopes, but caution against the use of DCs presenting only the former.
Schnell
S
S
Department of Human Genetics, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
Young
J W
JW
Houghton
A N
AN
Sadelain
M
M
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002645:Chickens; D018076:DNA, Complementary / Q000096:biosynthesis; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism* / Q000637:transplantation; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D005822:Genetic Vectors / Q000138:chemical synthesis / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000235:genetics; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008979:Moloney murine leukemia virus / Q000235:genetics*; D010047:Ovalbumin / Q000235:genetics / Q000276:immunology; D010455:Peptides / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
D018076:DNA, Complementary; D018984:Epitopes, T-Lymphocyte; D000949:Histocompatibility Antigens Class II; D010455:Peptides; D010047:Ovalbumin