Clonal deletion of simian virus 40 large T antigen-specific T cells in the transgenic adenocarcinoma of mouse prostate mice: an important role for clonal deletion in shaping the repertoire of T cells specific for antigens overexpressed in solid tumors.
In addition to their overexpression in cancer cells, most of the tumor-associated Ags are expressed at low but detectable levels in normal tissues. It is not clear whether the repertoire of T cells specific for unmutated tumor Ags is shaped by negative selection during T cell development. The transgenic adenocarcinoma of mouse prostate (TRAMP) model is transgenic for the SV40 large T Ag (Tag) under the control of the rat probasin regulatory elements. Although it has been established that T lymphocytes from TRAMP mice are tolerant to SV40 Tag, the mechanism of the tolerance is largely unknown. To examine whether the T cell clonal deletion is responsible for the tolerance, we crossed the TRAMP mice with mice transgenic for a rearranged TCR specific for SV40 Tag presented by the H-2K(k). Double transgenic TRAMP/TCR mice showed profound thymic deletion of SV40 Tag-reactive T cells, including a 6- to 10-fold reduction in the total thymocyte numbers and a >50-fold reduction in phenotypically mature T cells. Consistent with this finding, we observed that the SV40 Tag and endogenous mouse probasin genes are expressed at low levels in the thymus. These results demonstrate that clonal deletion is a major mechanism for tolerance to Ags previously regarded as prostate-specific, and provide direct evidence that the T cell repertoire specific for an unmutated tumor Ag can be shaped by clonal deletion in the thymus.
Zheng
Xincheng
X
Department of Pathology and Comprehensive Cancer Center, Ohio State University, Columbus 43210, USA.
Gao
Jian-Xin
JX
Zhang
Huiming
H
Geiger
Terrence L
TL
Liu
Yang
Y
Zheng
Pan
P
D000230:Adenocarcinoma / Q000235:genetics / Q000276:immunology*; D000595:Amino Acid Sequence; D000727:Androgen-Binding Protein / Q000096:biosynthesis; D000818:Animals; D000951:Antigens, Neoplasm / Q000096:biosynthesis* / Q000235:genetics; D000952:Antigens, Polyomavirus Transforming / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D002460:Cell Line; D017637:Clonal Deletion / Q000235:genetics*; D018984:Epitopes, T-Lymphocyte / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D005260:Female; D016056:Immunodominant Epitopes / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic / Q000235:genetics / Q000276:immunology*; D008969:Molecular Sequence Data; D011471:Prostatic Neoplasms / Q000235:genetics / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology / Q000378:metabolism / Q000821:virology
D000727:Androgen-Binding Protein; D000951:Antigens, Neoplasm; D000952:Antigens, Polyomavirus Transforming; D018984:Epitopes, T-Lymphocyte; D016056:Immunodominant Epitopes; C027519:probasin