Mechanism(s) of CD8 T cell-mediated Chlamydia-induced reproductive pathology

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 DESCRIPTION (provided by applicant): Chlamydial infections underlie the development of several clinically significant pathologies including blindness, female reproductive tract pathology cardiovascular diseases, and reactive arthritis. The long term goal of our research is to understand the mechanisms of chlamydial pathogenesis and prevent them. A vaccine is against Chlamydia is thought to be the ideal solution to prevent reproductive pathologies in the female upper genital tract (UGT). Since the host immune response or a subset is also responsible for these pathologies, the question arises: "How do we ensure that a vaccine does not inadvertently induce the pathologies that it was intended to prevent?" To this end, a deep understanding of chlamydial immunopathogenesis is needed, whereas it is currently incompletely understood. We have recently demonstrated various lines of evidence that antigen-specific, TNF-α producing, TNF receptor 2 expressing CD8+ T cells induce upper genital tract pathology following chlamydial infections. In this proposal, we will address the hypothesis that "Antigen- specific CD8+ T cells are a key regulator of pathogenic responses following chlamydial infections" and evaluate the modulation of such responses by protective vaccination regimens. The significance of addressing this hypothesis is as follows: A variety of immunological mediators have been shown to mediate chlamydial pathogenesis and our work demonstrates Chlamydia-specific CD8+ T cells as an additional mediator. Based on this, two important inferences can be made: (A) Various pathogenic mediators appear to function in a serial cascade since pathology can be significantly reduced by deleting one component, for example Ag-specific CD8+ T cells. This suggests that avoiding the elicitation of a key component in this pathway may be sufficient to reduce pathology, and (B) CD8+ T cells mediate pathology in an antigen (Ag)-specific fashion. Thus, the avoiding the elicitation of Ag-specific pathogenic CD8+ T cells would become a superior avoidance strategy when compared to innate immune mediators during preclinical and clinical trials of chlamydial vaccines. We will address our hypothesis with the following subaims: Aim 1. Determine whether Chlamydia-specific CD8+ T-cells engage neutrophils for pathogenesis. Aim 2. Determine whether protective vaccine regimens significantly reduce pathology by circumventing the pathogenic CD8+ T-cell response.