During the last funding period, we made an unexpected discovery-that antigen-specific CD8+ T cells with the phenotype and function of memory cells were generated within days after dendritic cell (DC) immunization. This contrasts with infection, where substantially longer time periods are required for memory cell development. We extended this observation by showing that injection of CpG DMA, a TLR9 agonist that induces robust inflammation similar to infection, prevents accelerated generation of memory CD8+ T cells after DC immunization. This suggests the intriguing hypothesis that early inflammation controls the rate of memory cell generation. Secondly, we show that even very weak primary CD8+ T cell responses generated by DC vaccination can be rapidly amplified by booster immunizations given as early as 4-6 days after the initial immunization. The upshot of this finding is that booster immunization can elevate numbers of secondary effector and memory cells much faster after DC immunization than with vaccines that rely on live pathogens or immunization with inflammatory adjuvants. The ability of vaccines to rapidly generate large numbers of effector and memory CD8+ T cells against weak antigens may be critical under some conditions, specifically in tumor immunotherapy or in response to bioterrorism. In summary, the long-term goal of this competitive renewal application is to understand the factors that regulate the rate of memory T cell formation and how accelerated memory generation after DC vaccination can be used to enhance vaccine efficacy. This information is directly relevant to the design of vaccines that will generate the fastest and most robust protective immunity against infection or tumors. We will address this goal through the following specific aims:
Aim 1. Determine the timing, identity and cellular targets of the inflammatory signals that control the rate of memory CD8+ T cell generation.
Aim 2. Evaluate accelerated memory and prime-boost after DC immunization for CD4+ T cell responses, DC subsets and diverse antigen sources.
Aim 3. Determine if accelerated memory and prime-boost after DC immunization improves immunotherapy against established tumors and protection against malaria and leishmaniasis. ? ?
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