Chlamydial genital infection is the most common bacterial sexually-transmitted disease in the U.S. and complications in women can result in infertility. The infection initiates at the epithelial surface of the genital mucosae, and associated fallopian tube or endometrial abnormalities manifest in epithelial tissues as well. Specific lymphocyte-epithelial interactions in the genital mucosa tissues lead to the acquisition of immunity or the onset of immunopathology. No studies have been reported that examined lymphoepithelial interactions associated with the elicitation of anti- chlamydial immune responses or how such interactions culminate in the intracellular inhibition of Chlamydia. By using a murine model of chlamydial genital infection and specifically-designed in vitro culture systems, this grant proposal is designed to investigate the cellular and molecular interactions, involving chlamydial-infected epithelial cells, chlamydial-specific T lymphocytes and their cytokines, that are required for controlling intraepithelial growth of Chlamydia in mice. Studies proposed would employ chlamydial-specific T cell clones, an in vitro model of the mucosal epithelium for studying epithelial-lymphocyte interactions, specific monoclonal antibodies directed at T cell-derived cytokines and adhesion molecules, inhibitors of anti-microbial processes induced by cytokines, and other molecular biologic and immunologic techniques to (a) identify protective chlamydial-specific T cells, (b) define the anti-microbial biochemical processes induced by T cell- derived cytokines (including tryptophan deprivation and nitric oxide production) that lead to intracellular inhibition of Chlamydia, and (c) analyze the epithelial-T cell interactions, involving cytokines, MHC and adhesion molecules, that contribute to intracellular inhibition of Chlamydia and promote local anti-chlamydial immunity. These studies will contribute to a better understanding of the cellular and molecular mechanisms of chlamydial immunity, which may be useful when designing a rational vaccine against Chlamydia.
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