2011-08-012024-05-17https://scholars.lib.ntu.edu.tw/handle/123456789/686982CD8+ T cells play a cardinal role in host defense against tumor. It has been reported that in hosts with tumors, the tumor-specific CD8+ T cell responses are usually weak. And, tumors have evolved some mechanisms to escape from host immunity, including downregulation of target antigens and antigen-presenting machinery. Therefore, to drive a complete differentiation program in CD8+ T cells, including clonal expansion and acquisition of effector functions, is crucial for eliminating tumor cells. However, the requirements for tumor-specific CTL priming in cancer hosts have not been well defined. Stimulating naïve CD8+ T cells with specific antigens and costimulatory signals is insufficient to induce optimal clonal expansion and effector functions. One recent report from my laboratory has demonstrated that a full CD8+ T cell response is elicited by a critical temporal function of IL-2 released from CD4+ T cells. The goal of this project is to study the molecular requirements for CD8+ T cell activation and differentiation to optimize T cell immunotherapy for cancer. The aims of the study are (1) to study whether TCR-peptide/MHC (TCR-pMHC) affinity determines CD28 costimulatory requirement for CD8+ T cell activation and differentiation and further affects the potency of tumor clearance in vivo; (2) to investigate whether high TCR-pMHC affinity overcomes the requirement for IL-2 signal during early priming of CD8+ T cells in vitro and in vivo; (3) to study whether CD28 costimulation synergizes with IL-2 signal during early priming of CD8+ T cells and renders the tumor-specific T effector cells capable of tumor killing. My intent in this study is to investigate whether the interplay of TCR-pMHC affinity, CD28 costimulation and IL-2 signal governs the threshold of CD8+ T cell activation and differentiation. Such approaches will advance our understanding of the regulation of a CD8+ T-cell response. It will also be of value in taking us one step closer to augment tumor-specific CD8+ T cell responses to optimize strategies of T cell immunotherapy for cancer.T cell immunotherapyCD8+ T cell activationTCR-pMHC affinityCD28