The goal of this project is to provide conditions required for the elimination of cancer cells by patient's CTLs. Despite the fact that tumor cells often express specific epitopes that could serve as targets for recognition and attack by CTL, tumors persist and grow. This reflects deficiencies in the available T-cell repertoire and/or the requirements necessary to promote an effective and sustained immune response that occur as a consequence of self-tolerance. The goal of this proposal is to identify differences between CTL specific for the same tumor expressed antigen that are obtained from conventional mice, or transgenic mice that express the tumor antigen as a self-protein in the periphery. CD8+ cells from TCR transgenics constructed using TCRs cloned from tolerant and non-tolerant animals, will provide an opportunity to follow the fate of T cells in vivo as a consequence of interaction with self-antigen and tumor expressed antigen. Mechanisms of T cell activation and persistence will be compared for tumors expressing high or low densities of the same antigen. Finally, conditions will be sought which maximize responsiveness and tumor elimination by tumor specific T cells that persist in the repertoire after self-tolerance.
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