Mechanisms of CD8+ T cell activation and memory maintenance following recombinant adenovirus immunization.

摘要

Recombinant viruses vaccine are promising tools for generating CD8+ T cell immunity. Vaccine optimization requires an in-depth understanding of the factors that control the maintenance and functionality of memory CD8+ T cells. Unlike most acute infections, the memory CD8+ T cell population elicited by recombinant human adenovirus serotype 5 (rHuAd5) vaccines displays a dominant effector memory phenotype, which is associated with prolonged antigen presentation. We recently reported that persistent, low-level transgene expression from the rHuAd5 vector was essential for maintaining the CD8+ T cell memory population. The work in this thesis focused on characterizing the location of antigen presentation following rHuAd5 immunization and investigating the types of antigen-presenting cells (APCs) required for the development ofCD8+ T cell memory in response to rHuAd5.;To determine whether the CD8+ T cell memory population could be influenced by changes in early signaling, we combined rHuAd5 vaccination with an agonist antibody against OX40 and the immunomodulatory drug, rapamycin, as both of these agents can promote the development of central memory CD8+ T cells. While each agent had some effect individually, when combined, the agents acted synergistically to increase both the quantity and polyfunctionality of the memory cell population. Consistent with this memory cell enhancement, the combination vaccine also improved immune protection. Limiting the duration of transgene expression from the rHuAd5 vector further enhanced skewing towards a central memory phenotype following OX40 plus rapamycin treatment, indicating that antigen exposure during the acute phase of the CD8+ T cell response plays a key role in defining the memory population.;Overall, these studies demonstrate that the memory CD8+ T cell pool develops as a composite of stimulations provided by both hematopoietic and non-hematopoietic cells and support a model where non-hematopoietic cells act as a source of long-term antigen required to sustain the CD8+ T cell memory produced by rHuAd5.;Within the lymphoid tissues, naïve CD8+ T cell priming occurred exclusively in the draining lymph nodes following rHuAd5 immunization and DCs played a key role in CD8+ T cell activation. The draining lymph nodes were important for primary expansion but not for memory maintenance. Even in the absence of the draining lymph nodes, persistence of antigen was required to maintain the memory CD8+ T cell population, suggesting antigen presentation by a non-lymphoid source. Using bone marrow chimeric mice, we determined that antigen presentation by non-hematopoietic APCs was sufficient for maintenance ofCD8+ T cell numbers. However, antigen presentation by this mechanism alone yielded a memory population with altered phenotype, cytokine production and protective capacity, indicating that antigen presentation through both hematopoietic and non-hematopoietic APCs ultimately defines the memory CD8+ T cell response produced by rHuAd5.