A tumor-associated and self antigen peptide presented by dendritic cells may induce T cell anergy in vivo, but IL-12 can prevent or revert the anergic state.
Ag-specific CD8+ cell responses, including delayed-type hypersensitivity in vivo and IFN-gamma production in vitro, are initiated by host immunization with P815AB, a self peptide bearing CTL epitopes and expressed by murine mastocytoma cells. Using P815AB-pulsed dendritic cells (DC) and monitoring class I-restricted skin test reactivity in DC-primed mice, we have previously shown that the development of a Th1-like response to P815AB requires T helper effects, such as those mediated by coimmunization with class II-restricted (helper) peptides or by the use of rIL-12. The adjuvanticity of IL-12 was suggested to involve improved recognition of class II-restricted epitopes of P815AB. In the present study, we provide evidence for the occurrence of I-A(d)-restricted epitopes in the tumor peptide. We also show that in the absence of helper peptide or rIL-12, P81 5AB not only failed to initiate CD8+ cell responses in vivo and in vitro, but resulted in a transient state of functional unresponsiveness, characterized by a profound inability of CD4+ cells to produce IL-2 in vitro. Ag-specific T cell anergy was also observed after neutralization of endogenous IL-12 at the time of priming with P815AB plus helper peptide. All of these effects were reversed by rIL-12, which was added to DC cultures and administered to the DC-recipient mice. Anergy induction may thus contribute to P81 5AB unresponsiveness in vivo. IL-12 may act to prevent or revert anergy to this tumor-associated and self peptide.
Grohmann
U
U
Department of Experimental Medicine, University of Perugia, Italy.
Bianchi
R
R
Ayroldi
E
E
Belladonna
M L
ML
Surace
D
D
Fioretti
M C
MC
Puccetti
P
P
D000818:Animals; D017951:Antigen Presentation; D000951:Antigens, Neoplasm / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology* / Q000637:transplantation; D018664:Interleukin-12 / Q000276:immunology* / Q000494:pharmacology; D051379:Mice; D008811:Mice, Inbred DBA; D011994:Recombinant Proteins / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D000951:Antigens, Neoplasm; D011994:Recombinant Proteins; D018664:Interleukin-12