Sexually transmitted diseases (STDs) pose one of the greatest threats to human lives worldwide, and yet there are no vaccines against STD agents. Currently, the process that leads to effective immune responses in the genital mucosa is poorly understood. Cytotoxic T lymphocyte (CTL) plays a pivotal role in defense against intracellular pathogens. The goal of the proposed study is to examine the anatomical, cellular and molecular mechanisms by which the antigen presenting dendritic cells (DCs) at the site of vaccination influence the establishment of effective CTL responses in the female genital mucosa. Toward this end, we propose to employ a mouse model of genital herpes in which the female mice are infected with herpes simplex virus (HSV) type 2 through its natural route of infection, the vaginal tract. In this proposal, we describe systematic approaches to examine how replication competent vs. defective attenuated HSV vaccines given via various immunization routes induce the mobilization of antigen-specific CD8+ T cells to the genital mucosa, and to analyze the importance of tissue DCs in conferring such capacities in CTLs. Further, the cellular requirement for the innate recognition of the viral vaccine vectors through Toll-like receptors will be examined.
The first aim will examine the expression of vaccine antigens and the role of DC subsets in CD8+ T cell priming following immunization through various routes of administration.
The second aim will examine how the DCs at the sites of immunization influences the distribution and function of memory CD8+ T cells in the vaginal mucosal tissues.
A final aim will determine the requirement for innate recognition of the vaccine vectors in establishing antiviral CTLs in the genital mucosa. Since productive establishment of CTL responses is important in defense against many intracellular STD agents, the knowledge gained from the proposed studies will provide critical basic and practical insights to a variety of STD vaccine approaches.
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