Transgenic Mice Developing Osteosarcomas Simian Virus 40 Large T Antigen Epitopes in T Antigen Sequential Loss of Cytotoxic T Lymphocyte Responses to

ABSTRACT The role of CTL tolerance in tumor immunity to SV40 large T antigen(T ag)-induced tumors was studied using T ag transgenic mice of the line501 (H2 b ). 501 mice express SV40 T ag under the influence of thea-amylase promoter, which leads to the development of osteogenic osteo-sarcomas late in life and eventual death between 12 and 17 months of age.We determined the ability of 501 mice to respond to the four H2 b -restricted T ag CTL epitopes, which include epitope I (T ag 206–215),epitope II/III (T ag 223–231), the immunorecessive epitope V (T ag489–497), restricted by H2-D b , and epitope IV (T ag 404–411), restrictedby H2-K b . We demonstrate that 501 mice are partially tolerant to theH2 b -restricted T ag epitopes. Immunization of 4-month-old 501 mice withT ag-transformed syngeneic cell lines or a recombinant vaccinia virusexpressing full-length T ag elicited CTL responses against the H2-K b -restricted T ag epitope IV only. In contrast, immunization of 4-month-old501 mice with recombinant vaccinia viruses expressing individual T agepitopes as minigenes elicited CTLs against epitopes I, IV, and V, but notagainst epitope II/III. Complete tolerance to epitopes I, IV, and V devel-oped in 501 mice, but the age when tolerance was detected varied for eachepitope. Tolerance to epitope I occurred by 6 months of age and wasaccelerated in the absence of CD4