Significance of the research. Vaccination with recombinant proteins is the safest way to immunize people against biological weapons and infectious diseases. However, the use of mild adjuvants with low levels of inflammatory side effects that make subunit vaccines desirable for immunization may also be responsible for their relatively poor efficacies. This is true because inflamed environments help promote the survival of activated T cells, which in turn promote long-term immunity. It is proposed that identification and description of adjuvant mechanisms that promote T cell survival will improve biodefensive vaccine design by favoring ways to maximize antigen-specific T cell yield while limiting inflammation. Research goals. This K02 application is organized around two research goals to be pursued in tandem over the next five years. The award will make possible Dr. Mitchell's scientific direction of experiments designed to determine i) the mechanisms by which Toll-like receptor (TLR) adjuvants promote T cell immunity via interactions with antigen-presenting cells, and ii) the signaling pathways in T cells that result from upstream interactions and that cause prolonged cellular survival. The hypothesis that TLR adjuvants boost the numbers of antigenspecific T cells by improving their survival through activities of the NF-kappaB/IkappaB factor Bcl-3 will be tested. Multiple aspects of this hypothesis will be tested using mouse models of T cell responses and infectious disease, microarray analyses, retroviral gene transfer, and biochemical analyses of experimentally modified T cells, in order to rationally enhance the establishment of immunity. Career development. Dr. Mitchell was first trained as a virologist and then as a T cell immunologist. He has an eight year history of studying the effects of adjuvants on T cells, and is poised to make significant advances in this subdiscipline. Career development will occur at the University of Louisville's Department of Microbiology, and at the Institute for Cellular Therapeutics, a center of excellence where the Mitchell laboratory is housed. The University of Louisville is a state-supported institution with a rapidly expanding basic research program. External salary support will lessen the load of non-research duties, such that conceptual advances in vaccine design for biodefense can be made.
