Innate lymphocytes in the female genital tract and their role in chlamydial infection

天然淋巴细胞(ILCs)群体在许多粘膜表面的作用已经被研究，并且它们的一些活性已经被研究出来，例如在肠道和呼吸道。女性生殖道也是一个坚实的粘膜表面，是许多病原体最初感染的地方。对女性和雌性小鼠生殖道下部和上部的ILC种群知之甚少，也几乎没有功能信息。沙眼衣原体是性传播疾病最常见的病原体，在年轻女性中发病率很高。沙眼衣原体最初通过宫颈上皮感染生殖道，但可以上升到子宫和输卵管，导致盆腔炎，导致严重的组织损伤。在小鼠模型中，衣原体感染在第一周以中性粒细胞渗入为特征，后来被T细胞取代。我们使用了报告小鼠阴道内感染鼠鼠的模型，该模型允许定义经典的(C)NKs、ILC1s和ILC3s。我们发现，CNK是生殖道内最大的稳态ILC，ILC1和ILC3的数量较少。感染鼠疫杆菌4天后，我们观察到ILC1s的大量扩张，CNKs和ILC3s的扩张较小，但仍很明显。在这一点上，观察到CNKS产生大量的干扰素-γ，ILC1产生大量的肿瘤坏死因子。我们假设，这种在感染早期的强烈反应有助于形成对衣原体的免疫反应，并有助于感染的发展和结局。在这个项目中，我们将通过追求三个具体目标来检验这一假设。首先，我们将根据细胞组成和特征、活性和效应器能力来表征生殖道中ILC的亚群。其次，我们将分析衣原体感染过程中激活这些ILC的上游信号。我们将确定在衣原体感染期间生殖道中的哪些细胞群产生关键的细胞因子(IL-12、-15和-18)，以及这些细胞因子对ILC的扩张和活性有哪些影响。第三，利用ILC耗竭的遗传模型，我们将努力计算ILC和ILC亚群对衣原体复制和抗衣原体防御、髓系和淋巴细胞免疫反应的形状、CD4记忆反应和组织损伤程度的重要性。我们相信，该项目的结果不仅将使我们深入了解ILC如何促进对一种重要的粘膜病原体的反应，而且还将提供有关该感染部位早期免疫反应的组织信息。

The role of populations of innate lymphocytes (ILCs) has been investigated at a number of mucosal surfaces and some of their activities have been worked out, for instance in the intestine and the respiratory tract. The female genital tract also is a substantial mucosal surface that serves as the site of initial infection for a number of pathogens. Very little is known about ILC-populations in the lower and higher genital tract in women and female mice, and almost no functional information is available. Chlamydia trachomatis is the most frequent bacterial agent of sexually transmitted disease with a high prevalence in young women. C. trachomatis initially infects the genital tract through the cervical epithelium but can ascend into the uterus and the oviducts and cause pelvic inflammatory disease, leading to substantial tissue damage. In a mouse model, chlamydial infection is during the first week characterised by a neutrophilic infiltrate, which is later replaced by T cells. We used the mouse model of intravaginal infection with C. muridarum in reporter mice that permit the definition of classical (c)NKs, ILC1s and ILC3s. We found that cNKs are the largest population of ILCs at steady state in the genital tract, with smaller populations of ILC1s and ILC3s. Four days after infection with C. muridarum we observed a massive expansion of ILC1s and smaller, still substantial, expansions of cNKs and ILC3s. Substantial production of IFN-gamma from cNKs and of TNF from ILC1s was observed at that point. We hypothesise that this strong response early in the infection contributes to the shape of the immune response to Chlamydia and to development and outcome of the infection. In this project we will test this hypothesis by pursuing three specific goals. First, we will characterize the subpopulations of ILCs in the genital tract in terms of cellular composition and characteristics, activity and effector capacity. Secondly, we will analyse the upstream signals activating these ILCs during chlamydial infection. We will establish which populations of cells in the genital tract produce key cytokines during chlamydial infection (IL-12, -15 and -18), and which effects these cytokines have on ILC expansion and activity. Thirdly, using genetic models of ILC-depletion we will endeavour to work out the importance of ILCs and ILC-subpopulations for chlamydial replication and anti-chlamydial defence, for the shape of the myeloid and lymphocytic immune response, the CD4 memory response and for the extent of tissue damage. We believe that the results of this project will permit insight not only into the ways how ILCs contribute to the response to an important mucosal pathogen but also will provide information on the organization of the early immune response at this relevant site of infection.