Dendritic cells, interleukin 12, and CD4+ lymphocytes in the initiation of class I-restricted reactivity to a tumor/self peptide.
Cell-mediated immunity involving CD8+ lymphocytes is effective in mediating rejection of murine mastocytoma cells bearing P815AB, a tumor-associated and self antigen showing similarity to tumor-specific shared antigens in humans. Although this antigen may act as an efficient target for class I-restricted responses in immunized mice, neither P815AB expressed on tumor cells nor a related synthetic nonapeptide will activate unprimed CD8+ cells for in vivo reactivity, measured by skin test assay. We review evidence showing that the failure of P815AB to initiate CD8+ cell reactivity may be due to defective recruitment of accessory and Th1-like cells to the afferent phase of the response initiated by transfer of mice with dendritic cells pulsed in vitro with the P815AB peptide. Although the copresence of a T helper peptide in dendritic cell priming in vitro with P815AB may compensate for the poor generation of accessory and Th1 cells in the adoptively transferred mice, recombinant IL-12 can replace the helper peptide in both effects. Effective priming to P815AB in vivo is achieved by either exposing dendritic cells to IL-12 prior to P815AB priming or administering the recombinant cytokine in vivo. Different approaches suggest that IL-12 may act both on accessory cells to improve presentation of previously undescribed class II-restricted epitopes of P815AB and on CD4+ cells to improve recognition of such epitopes. In particular, at the CD4+ cell level, IL-12 apparently acts as an adjuvant and an inhibitor of anergy induction. These data offer useful information for developing vaccination strategies using dendritic cells and class I-restricted tumor peptides in humans.
Grohmann
U
U
Department of Experimental Medicine, University of Perugia, Italy.
Fioretti
M C
MC
Bianchi
R
R
Belladonna
M L
ML
Ayroldi
E
E
Surace
D
D
Silla
S
S
Puccetti
P
P
D000276:Adjuvants, Immunologic; D000818:Animals; D017951:Antigen Presentation; D000951:Antigens, Neoplasm / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D017635:Clonal Anergy; D003713:Dendritic Cells / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D006801:Humans; D006968:Hypersensitivity, Delayed / Q000276:immunology; D018664:Interleukin-12 / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D010455:Peptides / Q000138:chemical synthesis / Q000276:immunology*; D011994:Recombinant Proteins / Q000276:immunology
D000276:Adjuvants, Immunologic; D000951:Antigens, Neoplasm; D018984:Epitopes, T-Lymphocyte; D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; D010455:Peptides; D011994:Recombinant Proteins; C076546:tumor rejection antigen P815A, mouse; D018664:Interleukin-12