T-Cell Mediated Immunity in Chlamydial Genital Infection

描述（由申请人提供）：沙眼衣原体感染仍然是盆腔炎的主要原因，并且经常导致人类输卵管损伤和不孕。虽然有有效的抗生素可用，但无症状感染可能会上升到上生殖道（GT），并在发现之前造成不可逆的组织损伤。避免上GT损伤的一个策略是通过预防性接种。然而，为了根除感染而产生的抗衣原体CD4 t -辅助性1型（Th1）应答也被认为参与了上GT损伤。该项目的目的是确定调节上肢GT衣原体免疫的机制，以更好地了解上肢GT损伤的基础。我们最近报道了CD4细胞主要被招募到上GT而不是下GT，并且在感染期间主要在上GT产生Th1引诱趋化因子。基于这些发现，我们假设上下GT募集T细胞的能力是不同的。我们还发现Th1细胞不是募集到GT的唯一亚群。在感染期间，产生IL-10的抗衣原体特异性T细胞也被募集到GT。分泌IL-10的T细胞可能会干扰Th1反应并加重上GT损伤。因此，验证这一假设，确定被招募到GT的产生IL-10的T细胞是否可以调节Th1对衣原体的反应，将是很重要的。为了验证这一假设，我们将1)确定控制Th1 CD4细胞向上GT增强募集的机制，2)确定改变Th1 CD4细胞募集是否能提高对衣原体感染的免疫力。3)确定产生IL-10的T细胞亚群（Th2, Tr1）是否阻碍抗衣原体Th1免疫。为了实现这些目标，我们将专注于鉴定介导Th1细胞募集到GT的趋化因子和趋化因子受体配体。此外，我们将尝试通过使用分泌Th1吸引趋化因子的腺病毒将这些Th1吸引趋化因子递送到阴道区域来增强下GT的免疫力。此外，通过IL-10敲除和转基因小鼠，我们将确定产生IL-10的T细胞亚群是否影响抗衣原体免疫和上GT损伤的发生。

DESCRIPTION (provided by applicant): Chlamydia trachomatis infection remains a major cause of pelvic inflammatory disease, and often leads to fallopian tube injury and infertility in humans. While effective antibiotics are available, asymptomatic infection may ascend to the upper genital tract (GT) and cause irreversible tissue damage before it is discovered. One strategy for avoiding injury to the upper GT is through preventative vaccination. However, the anti-chlamydial CD4 T-helper type 1 (Th1) response that develops to eradicate infection is also thought to participate in upper GT injury. The goal of this project is to identify mechanisms that regulate chlamydial immunity in the upper GT to better understand the basis of upper GT injury. We recently reported that CD4 cells are primarily recruited to the upper but not the lower GT and that Th1 attractant chemokines are produced primarily in the upper GT during infection. Based on those findings we hypothesize that the ability to recruit T cells differs between the upper and lower GT. We have also found that Th1 cells are not the only subset recruited to the GT. Anti-Chlamydia-specific T cells that produce IL-10 are also recruited to the GT during infection. T cells that secrete IL-10 may interfere with a Th1 response and enhance upper GT injury. Therefore, it will be important in validating the hypothesis to determine whether the IL-10 producing T cells that are recruited to the GT can modulate the Th1 response against Chlamydia. To test this hypothesis we will 1) Identify mechanism(s) that control the enhanced recruitment of Th1 CD4 cells to the upper GT, 2) Determine if altering Th1 CD4 cell recruitment improves immunity against Chlamydia infection. 3) Determine if IL-10 producing T cells subsets (Th2, Tr1) impede anti-chlamydial Th1 immunity. To achieve these goals, we will focus on identifying chemokine and chemokine receptor ligands that mediate Th1 cell recruitment to the GT. In addition, we will attempt to boost immunity in the lower GT by the delivery of these Th1-attractant chemokines to the vaginal region using adenoviruses that secrete Th1-atrractant chemokines. Also, using IL-10 knockout and transgenic mice we will determine whether IL-10 producing T cell subsets influence anti-Chlamydia immunity and the development of upper GT injury.