Peripheral tolerance to human papillomavirus E7 oncoprotein occurs by cross-tolerization, is largely Th-2-independent, and is broken by dendritic cell immunization

The E7 oncoprotein of human papillomavirus 16 functions as a tumor-specific antigen in transformed epithelial cells of the uterine cervix to which imm unotherapeutic strategies aimed at CTL induction may be directed. We previo usly have shown in mice transgenic for the E7 gene driven off an epithelial specific (keratin-14) promoter, that expression of E7 protein in periphera l epithelium is sufficient to tolerize E7-directed CTL precursors (pCTL; De an et nl,, J, Virol., 73: 6166-1670, 1999), Here we show that E7 is present ed to T cells for tolerization by cells of bone marrow origin ("cross-toler ization"). We demonstrate that tolerization of E7-directed pCTLs occurs wit hin 2 weeks of exposure to E7 in epithelium. It is maintained in the near a bsence of CD4(+) cells and in the absence of the thymus, and is independent of a coexisting E7-directed Th2-type antibody response. Tolerance was brok en by immunization with E7 CTL epitope-pulsed dendritic cells. These findin gs have implications for immunotherapy of patients with human papillomaviru s 16-associated cervical carcinoma, whose immune systems may have experienc ed long-term exposure to E7-expressing epithelial cells.