This proposal will explore several new observations in T cell biology that could potentially have a significant impact on the ability of vaccines to generate long-lived highly-functional memory CDS cells. First, it was recently demonstrated that the generation of functional memory CDS cells requires help from CD4 cells in the primary response. Second, interactions between CD40 and its ligand (CD 154) also appear to be important in the primary response for the generation of memory CDS T cells. Third, anti-CD40 antibodies have been shown to promote primary CDS responses to a wide variety of normally non-immunogenic antigens. Together, these observations suggest that CD4 cells provide help to CDS cells by expressing CD154 and signaling through CD40. In addition, these observations suggest that anti-CD40 may substitute for CD4 help and act as a potent adjuvant for vaccines that are designed to elicit long-lived highly-functional memory CDS cells. However, the relationship between CD4 help and CD40 signaling remains unclear and the cell types that require CD40:CD154 interactions to promote the development of memory CDS cells are unknown. Moreover, the ability of anti-CD40 antibodies to substitute for CD4 help in the development of memory CDS cells has never been tested and the mechanisms by which these antibodies work are undefined. Therefore, the experiments in this proposal will define how CD4 help and CD40 signaling are related and how they contribute to the development of influenza-specific memory CDS cells. In addition, the experiments in this proposal will test the ability of anti-CD40 antibodies to substitute for CD4 help in the generation of memory CDS cells and will define the mechanisms by which those antibodies work. Together, these experiments will provide the foundation for the development of vaccines that elicit long-lived highly-functional memory CDS T cells. ? ? ?
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