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

描述（由申请人提供）：由沙眼衣原体引起的性传播疾病，一种细胞内细菌病原体，影响全球约9000万人。在未经治疗的妇女中，这些感染会引起严重的后遗症，如盆腔炎和异位妊娠，往往导致不孕。我们研究的长期目标是了解衣原体的发病机制并加以预防。预防这类后遗症的疫苗被认为是解决这一问题的理想方法，目前的工作重点是鉴定诱导CD8+ T细胞强烈反应的衣原体抗原，因为CD8+ T细胞通常在清除细胞内病原体方面是有效的。然而，我们最近发现CD8+ T细胞能够产生TNF-a介导上生殖道（UGT）病理，但在小鼠生殖器衣原体感染后对衣原体清除的贡献很小。TNF-a通过两种主要受体TNF-受体1 （TNFR1）和TNFR2诱导包括细胞凋亡在内的多营养效应，在不同的感染模型中，这两种受体已被证明是互补或对立的。因此，TNFR1的具体贡献

DESCRIPTION (provided by applicant): Sexually transmitted diseases caused by Chlamydia trachomatis, an intracellular bacterial pathogen, affect approximately 90 million people worldwide. In untreated women, these infections cause serious sequelae such as pelvic inflammatory disease and ectopic pregnancy, often resulting in infertility. The long term goal of our research is to understand the mechanisms of chlamydial pathogenesis and prevent them. A vaccine to prevent such sequelae is thought to be an ideal solution to the problem, and efforts are focused on identifying of chlamydial antigens that induce a robust CD8+ T cell response, since CD8+ T cells are typically effective in clearance of intracellular pathogens. However, we have found recently that CD8+ T cells capable of producing TNF-a mediate upper genital tract (UGT) pathology, but contribute minimally to chlamydial clearance, following genital chlamydial infection in mice. TNF-a induces pleotrophic effects including apoptosis via two main receptors, TNF receptor 1 (TNFR1) and TNFR2, which have been shown to complement or oppose the effects of each other in different infection models. Therefore, the specific contributions of TNFR1 and TNFR2 in chlamydial pathogenesis need to be determined to explore therapeutic approaches in the future. We also have found that Chlamydia-specific, not na¿ve, CD8+ T cells mediate the genital pathologies. CD8+ T cells contribute minimally to chlamydial clearance possibly due to down- regulation of MHC class I expression on Chlamydia-infected cell surfaces. Given this, it appears that Chlamydia-specific CD8+ T cells do not target infected cells efficaciously and consequently contribute minimally to chlamydial clearance; nevertheless, they get activated and cause pathology possibly by targeting uninfected cells. This suggests the possibility that chlamydial peptides are presented to CD8+ T cells by uninfected cells, but begs the question: "How do uninfected cells acquire chlamydial peptides"? The phenomenon of gap junction mediated antigen transport (GMAT) may explain this paradigm. GMAT occurs via channels formed by connexin (Cx) proteins, predominantly Cx43 (expressed by the gap junction alpha 1 gene, or Gja1). Connexin 43, also expressed on oviduct epithelium, has been shown to be involved in the transfer of antigenic peptides from infected to bystander uninfected cells and subsequent presentation to CD8+ T cells. Such a mechanism would explain both the pathological effects and low efficiency of chlamydial clearance mediated by this cell type. However, the role of Cx43 and GMAT in microbe-induced immunopathogenesis in vivo systems has yet to be demonstrated. Based on this, we will test our central hypothesis that "CD8+ T cells mediate chlamydial reproductive pathology through TNF-a receptors and target uninfected cells". We will test this hypothesis by: Aim 1. Determine the role of TNF-a receptors in CD8+ T cell mediated chlamydial pathogenesis, and Aim 2. Determine the role of connexin 43 in CD8+ T cell mediated chlamydial pathogenesis