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Supria Sarma^*, Yong Guo^*, Yannik Guilloux^*, Cheng Lee^*, Xue-Feng Bai^*,, and Yang Liu^*,

From the ^* Department of Pathology and Kaplan Comprehensive Cancer Center, New York University Medical Center, New York 10016; and the Department of Pathology and Comprehensive Cancer Center, Ohio State University Medical Center, Columbus, Ohio 43210

Unmutated tumor antigens are chosen as primary candidates for tumor vaccine because of their expression on multiple lineages of tumors. A critical issue is whether unmutated tumor antigens are expressed in normal cells, and if so, whether such expression imposes special restrictions on cytotoxic T lymphocyte (CTL) responses. In this study, we use a transgenic approach to study the development and effector function of T cells specific for P1A, a prototypical unmutated tumor antigen. We report here that although P1A is expressed at low levels in normal tissues, including lymphoid tissues, the P1A-specific transgenic T cells develop normally and remain highly responsive to the P1A antigen. The fact that transgenic expression of P1A antigen in the thymus induces T cell clonal deletion demonstrates that normal hematopoietic cells can process and present the P1A antigen and that P1A-specific T cells are susceptible to clonal deletion. By inference, P1A-specific T cells must have escaped clonal deletion due to low expression of P1A in the thymus. Interestingly, despite the fact that an overwhelming majority of T cells in the T cell receptor for antigen (TCR)–transgenic mice are specific for P1A, these mice are no more resistant to a P1A-expressing plasmocytoma than nontransgenic littermates. Moreover, when the same TCR-transgenic mice were challenged simultaneously with B7-1⁺ and B7-1^– tumors, only B7-1⁺ tumors were rejected. Therefore, even though P1A can be a tumor rejection antigen, the effector function of P1A-specific CTL is restrained in vivo. These results have important implications for the strategy of tumor immunotherapy.

Key Words: cytotoxic T lymphocytes • unmutated tumor antigen • T cell development • antitumor immunity • T cell receptor–transgenic mice

This study is supported by grants from the National Institutes of Health (NIH) (CA58033 and CA69091), Kaplan Comprehensive Center of New York University Medical Center, and Ohio State University Comprehensive Cancer Center. Part of the study was carried out when Supria Sarma was supported by NIH training grant CA09161.

Present addresses are as follows: S. Sarma, Howard Hughes Medical Institute, Rockefeller University, 1230 York Ave., New York, NY 10021; Y. Guo, Hoechst Marion Rousse, Inc., CNS-Molecular Biology, Bridgewater, NJ 08807; C. Lee, 3161 Broadway, Apt. 6C, New York, NY 10027; X.-F. Bai, Department of Pathology, Ohio State University Medical Center, 146 Hamilton Hall, 1645 Neil Ave., Columbus, OH 43210; and Y. Guilloux, Institut de Biologie, INSERM U463, 9 Quai, Moncousu, 44093, Nantes cedex 1, France.

S. Sarma, Y. Guo, Y. Guilloux, and X.-F. Bai contributed equally to this study.

Abbreviations used: E_µ, IgM heavy chain enhancer; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; RT, reverse transcriptase; SW, Swiss Webster; TG, transgenic mouse.

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