PROJECT SUMMARY Infection with Chlamydia trachomatis is responsible for significant morbidity and healthcare costs throughout the world. Work from our lab has demonstrated that T cells are a key mediator of immune protection against C. trachomatis. Our long-term goal has been to gain an understanding of how CD8+ T cells are stimulated in response to C. trachomatis infection. The reagents we have developed have allowed us to use contemporary approaches in cellular immunology to define how Chlamydia-specific T cells respond to infection. We have shown that transfer of cultured Chlamydia-specific CD8+ T cells into mice can protect against infection, yet surprisingly, a protective CD8+ T cell memory response is not stimulated following natural infection of mice or people. The apparent failure of the adaptive immune system to effectively clear the organism and/or prevent repeat infection is a hallmark of human infection with C. trachomatis, resulting in sequelae of infection such as permanent reproductive tract damage. Consistent with these findings in humans, we have observed that CD8+ T cells respond extremely well to primary infection, yet the memory cells that result from initial infection have impaired recall during subsequent encounters with the organism. Here, our goal is to 1) understand the mechanism by which CD8+ T memory is inhibited during infection and develop methods to overcome it, and 2) identify vaccine formulations that stimulate protective CD8+ T cells and test their capacity to enhance vaccine-mediated CD4+ T cell immunity. The vaccine strategies we will use build on a successful experimental approach using nanoparticles encapsulating an adjuvant and bound to whole inactivated organisms. Ultimately, we anticipate this work will drive selection of appropriate strategies for vaccine development that provide robust protection against C. trachomatis.