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 hypersensiti vity in vivo and IFN-gamma production in vitro, are initiated by host immunization with P815AB, a self peptide bearing CTL epitopes and expr essed by murine mastocytoma cells, Using P815AB-pulsed dendritic cells (DC) and monitoring class I-restricted skin test reactivity in DC-pri med mice, we have previously shown that the development of a Th1-like response to P815AB requires T helper effects, such as those mediated b y coimmunization with class II-restricted (helper) peptides or by the use of rIL-12. The adjuvanticity of IL-12 was suggested to involve imp roved recognition of class II-restricted epitopes of P815AB. In the pr esent study, we provide evidence for the occurrence of I-Ad-restricted epitopes in the tumor peptide. We also show that in the absence of he lper peptide or rIL-12, P815AB 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 a lso observed after neutralization of endogenous IL-12 at the time of p riming with P815AB plus helper peptide. All of these effects were reve rsed by rIL-12, which was added to DC cultures and administered to the DC-recipient mice. Anergy induction may thus contribute to P815AB unr esponsiveness in vivo. IL-12 may act to prevent or revert anergy to th is tumor-associated and self peptide.