T-cell mediated immunity in chlamydia genital infection

描述（由申请人提供）：沙眼衣原体是一种专性细胞内细菌，引起大多数细菌性性传播感染（STI）。在美国，每年发生300万新的感染病例，通常导致盆腔炎（PID）、异位妊娠和输卵管不孕症，每年花费医疗保健行业数十亿美元。调节性T细胞（Tcells）具有抑制T细胞应答和防止宿主组织炎症的能力。设计一种限制上生殖道（UGT）炎症的方法可能会预防衣原体感染后的后遗症。我们已经确定了CD 4 + FoxP 3 + T细胞亚群和CD 8 + CXCR 5 + T细胞亚群，它们在衣原体生殖器感染期间出现在重叠但不同的位置，并可能通过不同的方式影响感染。我们的初步数据表明，CD 4 + FoxP 3 + T细胞存在于生殖道和次级淋巴组织感染期间。pDC数量的减少改变了衣原体生殖器感染过程中Th 1/T细胞的平衡，表明pDC参与了CD 4 + FoxP 3 + T细胞的产生。相比之下，在感染之前，CD 8 + CXCR 5 + T细胞存在于未感染小鼠中。衣原体感染后，CD 8 + CXCR 5 + T细胞的缺乏导致输卵管周围淋巴细胞的大量聚集和胶原沉积。感染通过诱导FoxP 3的表达、调节体内MoPn应答性T细胞的细胞因子分泌以及逆转UGT中的淋巴细胞积累和胶原沉积来刺激THP功能。总而言之，我们假设FoxP 3 +Tregs调节衣原体感染和UGT组织炎症，并提出以下具体目标：1.确定CD 8 + CXCR 5 + T细胞控制衣原体生殖器感染的机制。2.探讨CD 4 + FoxP 3 + T细胞在生殖道衣原体感染中的作用。我们将通过体内和体外的生殖器感染实验来验证这些目的。沙眼衣原体（MoPn）、过继转移、流式细胞术、ELISA和使用CXCR 5和FoxP 3-Delta-EGFP敲除和FoxP 3-GFP敲入、OT-II转基因小鼠和FoxP 3-DTR和CD 11 c-DTR的条件性敲除的CFSE T细胞抑制剂测定。宿主组织炎症的病因学研究也将促进其他感染、移植排斥和自身免疫反应后免疫介导的病理学的预防。了解THBE在UGT炎症中的作用对于开发衣原体感染和其他STI的新型免疫调节疗法至关重要。PI，Kathleen A博士。Kelly在研究衣原体感染后的小鼠UGT炎症方面具有独特的经验，并组建了一个团队，这将使她能够做出重大贡献。公共卫生相关性：沙眼衣原体（Chlamydia trachomatis）是一种专性细胞内细菌，在美国引起大多数细菌性性传播感染（STI）病例，每年可导致约一百万例免疫介导的盆腔炎（PID）和/或感染女性不孕症。治疗PID和不孕症每年给美国医疗保健系统带来数十亿美元的负担，这项提案研究了一种潜在的方法（FoxP 3 + T调节细胞），可以减少衣原体性传播感染后发生免疫介导的后遗症的个体数量。

DESCRIPTION (provided by applicant): Chlamydia trachomatis, an obligate intracellular bacterium, causes the most cases of bacterial sexually transmitted infections (STIs). Three million new cases of infection occur in the US each year and commonly result in pelvic inflammatory disease (PID), ectopic pregnancy and tubal infertility which costs the health care industry billions of dollars annually. Regulatory T cells (Tregs) have the ability to suppress T cell responses and prevent host tissue inflammation. Devising a means for limiting inflammation in the upper genital tract (UGT) would likely prevent the sequelae that follow chlamydial infection. We have identified CD4+FoxP3+Tregs and CD8+CXCR5+Tregs that appear in overlapping but different locations during chlamydial genital infection and likely influence infection by distinct means. Our preliminary data indicates that CD4+FoxP3+Tregs are present during infection in the genital tract and secondary lymphoid tissue. Reduction in the number of pDC alters the balance of Th1/Tregs during chlamydial genital infection and suggests that pDC are involved in production of CD4+FoxP3+Tregs. In contrast, CD8+CXCR5+Tregs cells are present in naove mice prior to infection. The lack of CD8+CXCR5+Tregs result in marked lymphocyte accumulation and collagen deposition surrounding oviducts after chlamydial infection. Infection stimulates Tregs function by inducing the expression of FoxP3, regulating cytokine secretion by MoPn-responsive T cells in vivo and reversing lymphocyte accumulation and collagen deposition in the UGT. Taken together, we hypothesize that FoxP3+Tregs regulate chlamydial infection and UGT tissue inflammation and propose the following specific aims: 1. Identify mechanism(s) by which CD8+CXCR5+ Tregs control chlamydial genital infection. 2. Evaluate the contribution of CD4+FoxP3+Tregs on Chlamydia genital infection. We will test these Aims with in vivo and in vitro experiments of genital infection with the mouse agent of C. trachomatis (MoPn), adoptive transfer, flow cytometry, ELISA, and CFSE Tregs suppressor assays using CXCR5 & FoxP3-Delta-EGFP knockout & FoxP3-GFP knockin, OT-II transgenic mice and the conditional knockouts for FoxP3-DTR & CD11c-DTR. Investigation of the etiology of host tissue inflammation will also advance the prevention of immune-mediated pathology following other infections, transplantation rejection and autoimmune reactions. Understanding the role of Tregs in UGT inflammation is essential for developing novel immunomodulatory therapeutics for chlamydial infection and other STI's. The PI, Dr. Kathleen A. Kelly is uniquely experienced to investigate murine UGT inflammation following Chlamydia infection and has assembled a team which will enable her to make significant contributions. PUBLIC HEALTH RELEVANCE: Benefits for Public Health Chlamydia trachomatis, an obligate intracellular bacterium, causes the most cases of bacterial sexually transmitted infections (STIs) in the US and can result in about one million cases of immune- mediated pelvic inflammatory disease (PID) and/or infertility in infected females annually. Treating PID and infertility burdens the US health care system by billions of dollars annually and this proposal examines a potential means (FoxP3+ T regulatory cells) of reducing the number of individuals which develop immune-mediated sequelae following Chlamydia STIs.