Date of Award

2014

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Cell & Molecular Biology

First Advisor

Hildegund C. Ertl

Abstract

Vaccines against some of the most pervasive pathogens, including HIV, TB, and malaria, are desperately needed. Available evidence suggests that both central memory and effector CD8+ T cells play a role in mediating protective immunity against many pathogens. Recombinant adenoviruses currently under development as vaccine carriers induce potent and sustained transgene product-specific CD8+ T cell responses. The transgene product-specific CD8+ T cell response remains activated and is delayed in transitioning to central memory. Here we investigate how this response is maintained.

Adenoviral vectors persist and remain transcriptionally active in vivo. We investigated the role that continuous transgene expression plays in maintaining the effector memory-biased transgene product-specific CD8+ T cell response. Dual expression vectors based on AdC7 expressing transgenes that could be regulated temporally were generated. Vectors were unexpectedly unstable in vivo. Alternatively we inhibited the mTOR pathway, which is downstream of the T cell receptor and has recently been implicated in memory development, using a low dose of rapamycin. Rapamycin failed to enhance the quality of the transgene-product specific CD8+ T cells.

Persisting transgene product could maintain the transgene product-specific CD8+ T cell response by continual recruitment of naïve CD8+ T cells, similar to some other persistent viruses. However, in an adoptive transfer model, we demonstrate that the response is primarily maintained by antigen-experienced cells that do not lose function over time.

Pre-existing anti-adenovirus immunity is common, particularly for the human adenoviruses currently in development as vaccine carriers. Here we demonstrate that pre-existing anti-adenovirus neutralizing antibodies accelerate and enhance transgene product-specific CD8+ T cell differentiation into central memory. These cells were highly functional and responded robustly to booster immunization. Importantly, this may be due in part to a reduction the vector's reservoir in T cells.

These data suggest that further study of transgene product expression and its functional impact on immune responses is necessary. Further understanding this impact will allow manipulation of immune responses induced by the adenovirus vaccine platform such that they can be tailored to specific pathogens.

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