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Immunology |
Department of Microbiology and Immunology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033 [T. D. S., S. S. T.], and The Jackson Laboratory, Bar Harbor, Maine 04609 [B. B. K.]
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 line
501 (H2b). 501 mice express SV40 T ag under
the influence of the 
-amylase promoter, which leads to the
development of osteogenic osteosarcomas 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 H2b-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 ag 489–497), restricted by
H2-Db, and epitope IV (T ag 404–411), restricted by
H2-Kb. We demonstrate that 501 mice are partially tolerant
to the H2b-restricted T ag epitopes. Immunization of
4-month-old 501 mice with T ag-transformed syngeneic cell lines or a
recombinant vaccinia virus expressing full-length T ag elicited CTL
responses against the H2-Kb-restricted T ag epitope IV
only. In contrast, immunization of 4-month-old 501 mice with
recombinant vaccinia viruses expressing individual T ag epitopes as
minigenes elicited CTLs against epitopes I, IV, and V, but not against
epitope II/III. Complete tolerance to epitopes I, IV, and V developed
in 501 mice, but the age when tolerance was detected varied for each
epitope. Tolerance to epitope I occurred by 6 months of age and was
accelerated in the absence of CD4+ T cells. Tolerance to
the immunorecessive epitope V was observed in 12-month-old 501 mice but
was independent of the presence of osteosarcomas. In contrast, CTLs
specific for epitope IV were detected in mice from 3 to 14 months of
age but not in mice that had developed osteosarcomas. Analysis of
epitope IV-specific CD8+ cells derived from 3-month-old 501
mice with H2-Kb/epitope IV tetramers revealed decreased
numbers of epitope IV-specific CD8+ cells in 501 mice
relative to C57BL/6 mice, with a further decrease in older 501 mice.
Tumor progression resulted in loss of H2-Kb/epitope IV
tetramer staining CD8+ cells. Thus, progression to
tolerance to individual T ag CTL epitopes in 501 mice is epitope
dependent.
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