Cytotoxic T lymphocytes to an unmutated tumor rejection antigen P1A: normal development but restrained effector function in vivo

S Sarma, Y Guo, Y Guilloux, C Lee, XF Bai… - The Journal of …, 1999 - rupress.org
S Sarma, Y Guo, Y Guilloux, C Lee, XF Bai, Y Liu
The Journal of experimental medicine, 1999rupress.org
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 …
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.
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