IL-12 is both required and sufficient for initiating T cell reactivity to a class I-restricted tumor peptide (P815AB) following transfer of P815AB-pulsed dendritic cells.
Delayed-type hypersensitivity responses, mediated by CD8+ cells and detected by skin test assay, occur in sensitized mice in response to challenge with a class I-restricted synthetic peptide related to a poorly immunogenic tumor rejection Ag, P815AB, of murine mastocytoma cells. Efficient priming for this response, which requires functional CD4+ cells and production of IFN-gamma in the host, is achieved by transfer of dendritic cells (DC) pulsed in vitro with a physical mixture of P815AB and T helper peptides, such as a class II-restricted synthetic peptide of tetanus toxin. We now show that the adjuvant effect of the T helper peptide was associated with the appearance of early and late IL-12 transcripts in the spleens of DC recipient mice, correlated with a late IFN-gamma response, and was negated by serologic ablation of endogenous IL-12 at the time of cell transfer. rIL-12, administered in vivo to the DC recipient mice, could substitute for the T helper peptide in initiating skin test reactivity following transfer of DC pulsed with P815AB alone, leading to Ag-specific production of IFN-gamma by CD4+ and CD8+ T cells. In vitro and in vivo cell depletion experiments suggested the following: 1) the exogenous IL-12 required both CD4+ and CD8+ cells for activity; 2) the immune response initiated by IL-12 relied on later production of IL-12 by the host; and 3) the early adjuvanticity of the exogenous IL-12 involved improved recognition of class II-restricted epitopes of this otherwise poorly immunogenic tumor peptide.
Bianchi
R
R
Department of Experimental Medicine, University of Perugia, Italy.
Grohmann
U
U
Belladonna
M L
ML
Silla
S
S
Fallarino
F
F
Ayroldi
E
E
Fioretti
M C
MC
Puccetti
P
P
D000276:Adjuvants, Immunologic; D000595:Amino Acid Sequence; D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology* / Q000637:transplantation; D006183:H-2 Antigens / Q000276:immunology*; D064532:Histocompatibility Antigen H-2D; D000949:Histocompatibility Antigens Class II / Q000276:immunology*; D006968:Hypersensitivity, Delayed / Q000276:immunology*; D007114:Immunization; D016219:Immunotherapy, Adoptive; D007371:Interferon-gamma / Q000096:biosynthesis / Q000378:metabolism; D018664:Interleukin-12 / Q000502:physiology*; D015847:Interleukin-4 / Q000096:biosynthesis / Q000378:metabolism; D008212:Lymphocyte Depletion; D008297:Male; D012515:Mast-Cell Sarcoma / Q000276:immunology / Q000473:pathology; D051379:Mice; D008811:Mice, Inbred DBA; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000276:immunology*; D010446:Peptide Fragments / Q000276:immunology*; D011994:Recombinant Proteins / Q000494:pharmacology; D012882:Skin Tests; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D013744:Tetanus Toxin / Q000276:immunology
D000276:Adjuvants, Immunologic; D000951:Antigens, Neoplasm; D006183:H-2 Antigens; D064532:Histocompatibility Antigen H-2D; D000949:Histocompatibility Antigens Class II; D009363:Neoplasm Proteins; D010446:Peptide Fragments; D011994:Recombinant Proteins; D013744:Tetanus Toxin; C076546:tumor rejection antigen P815A, mouse; D018664:Interleukin-12; D015847:Interleukin-4; D007371:Interferon-gamma