Peripheral tolerance to human papillomavirus E7 oncoprotein occurs by cross-tolerization, is largely Th-2-independent, and is broken by dendritic cell immunization
T. Doan et al., Peripheral tolerance to human papillomavirus E7 oncoprotein occurs by cross-tolerization, is largely Th-2-independent, and is broken by dendritic cell immunization, CANCER RES, 60(11), 2000, pp. 2810-2815
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.