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.

Abstract

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.

• Authors: Xincheng Zheng, Jian-Xin Gao, Huiming Zhang, Terrence L Geiger, Yang Liu, Pan Zheng
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 169 Issue 9 Pg. 4761-9 (Nov 01 2002) ISSN: 0022-1767 [Print] United States
• PMID: 12391185 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Androgen-Binding Protein
• Antigens, Neoplasm
• Antigens, Polyomavirus Transforming
• Epitopes, T-Lymphocyte
• Immunodominant Epitopes
• probasin

Topics

• Adenocarcinoma (genetics, immunology)
• Amino Acid Sequence
• Androgen-Binding Protein (biosynthesis)
• Animals
• Antigens, Neoplasm (biosynthesis, genetics)
• Antigens, Polyomavirus Transforming (biosynthesis, genetics, immunology)
• Cell Line
• Clonal Deletion (genetics)
• Epitopes, T-Lymphocyte (biosynthesis, genetics, immunology)
• Female
• Immunodominant Epitopes (immunology)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic (genetics, immunology)
• Molecular Sequence Data
• Prostatic Neoplasms (genetics, immunology)
• T-Lymphocyte Subsets (immunology, metabolism, virology)
• Thymus Gland (cytology, immunology, metabolism, virology)