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，并经常导致输卵管损伤和不孕症。虽然有效的抗生素是可用的，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损伤的一种策略是通过预防性疫苗接种。然而，抗衣原体CD 4辅助性T细胞1型（Th 1）反应，发展消除感染也被认为是参与上GT损伤。本项目的目标是确定机制，调节衣原体免疫上GT，以更好地了解上GT损伤的基础。我们最近报道，CD 4细胞主要募集到上部，但不是下部GT和Th 1型趋化因子的产生主要是在上部GT感染期间。基于这些发现，我们假设上GT和下GT招募T细胞的能力不同。我们还发现Th 1细胞并不是招募到GT的唯一子集。产生IL-10的抗衣原体特异性T细胞也被招募到GT感染期间。分泌IL-10的T细胞可能干扰Th 1应答并增强上GT损伤。因此，重要的是验证假设，以确定是否IL-10产生的T细胞募集到GT可以调节对衣原体的Th 1应答。为了验证这一假设，我们将1）确定控制Th 1 CD 4细胞向上GT募集增强的机制，2）确定改变Th 1 CD 4细胞募集是否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（Th 2，Tr 1）是否阻碍抗衣原体Th 1免疫。为了实现这些目标，我们将集中精力确定趋化因子和趋化因子受体配体介导的Th 1细胞招聘的GT。此外，我们将试图提高免疫力，在较低的GT通过交付这些Th 1趋化因子的阴道区域使用腺病毒分泌Th 1-atractant趋化因子。此外，使用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损伤的发展。

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.