CD8+ T cells (TCD8+) play a key role in combating intracellular infections, by recognizing short fragments of the pathogen (epitopes) at the surface of the infected cell and bringing about the cell's destruction. In this way, spread of the infection is brought under control. Despite such activity and the fact that vaccine strategies are increasingly taking this subset of the immune system into account, much remains to be understood regarding primary TCD8+ responses and the establishment and maintenance of antigen-specific TCD8+ memory. In this application, the applicant focuses on impact that cell surface epitope density has upon primary TCD8+ responses as well as the establishment and maintenance of memory, hypothesizing that the impact is significant with regard to all three areas. He has developed a panel of recombinant vaccinia viruses that permits widely varied expression of four well-defined class I-restricted epitopes in the context of a constant viral challenge, a prerequisite for testing the hypothesis. He will exploit this panel in combination with several assays for TCD8+ activation and function to determine the impact of epitope density on the following parameters: 1) The activity of the primary response. Our prediction is that low epitope density will elicit high avidity TCD8+, intermediate epitope density, both high and low avidity TCD8+, and very high epitope density, only low avidity TCD8+. 2) The cytokines released by responding TCD8+. He expects that, for all but the highest epitope densities, responses will be TC1 (interferon-g-producing). 3) The number of TCD8+ entering the memory pool. He expects this will be a direct consequence of epitope density in the primary challenge. 4) Reversion of memory cells from the activated (tissue homing) to naïve (lymph node homing) phenotype. He predicts that the kinetics of reversion will be independent of epitope density. 5) The avidity and cytokine-producing potential of memory TCD8+ that we expect will mirror the primary response. 6) Secondary responses to heterologous and homologous rechallenge. The applicant predicts secondary responses will be strongly influenced by epitope density at both the primary and secondary phases. He anticipates that in following the outlined plan, many more questions will be raised. Already he sees a number of permutations that are worth pursuit at a later date. These include studies on different routes of administration, different vectors and the issue of protection from lethal challenge. He believes that the pursuit of these aims will provide fundamentally important information about TCD8+-mediated immunity and will put us in a strong position to address the next generation of questions that will be facing the field.
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