Influence of sex-steroid and microbiome on female genital resident memory T cell development

女性生殖道粘膜表面是病原体复制的常见部位。许多 这些病原体建立性传播感染（STIs），这是一种隐藏的流行病， 这是一个令人担忧问题。许多性病，包括艾滋病毒和单纯疱疹病毒（HSV），缺乏 治疗性疗法，并将极大地受益于预防性疫苗接种。抗HIV和HSV-2疫苗试验 那些仅仅专注于产生中和抗体的方法迄今未能提供显著的保护作用， 效益越来越多的人认识到，有效的粘膜疫苗方案应能同时激发两种抗体 和T细胞。常驻记忆T细胞（TRM）是生殖器粘膜中的主要T细胞群，代表了一种免疫应答。 对细胞内病原体的主要防御机制。与循环记忆T细胞相反，TRM 在其来源组织中建立永久居留，不通过血液和淋巴进行常规循环。 在啮齿动物和非人灵长类动物模型中的还原实验表明， 粘膜TRM位于感染部位附近。因此，建立大量的高功能 FRT中的CD 8 TRM介导快速病原体清除是许多疫苗接种的关键长期目标 程序.然而，实现足够数量和质量的粘膜TRM取决于详细的 了解这些细胞的分化和维持需求。最近已经 认识到当地环境是TRM差异化计划的重要贡献者， 他们的长期维护。我们的初步数据表明雌激素在影响FRT TRM中起着关键作用 阵这项建议的总体目标是询问性激素和局部激素的贡献。 微生物组在塑造FRT TRM隔室中的作用。在第一个目标下，我们将利用简化的小鼠模型， 研究CD 8 T细胞内在雌激素信号传导在FRT TRM建立中的作用的方法。 在第二个目标中，我们将使用无菌小鼠和微生物组耗竭方法来检查 对TRM形成和功能的影响。确定有助于TRM的当地因素 分化和功能将有助于开发方法，以在肿瘤细胞中产生稳健的T细胞应答。 生殖粘膜

The mucosal surface of female reproductive tract (FRT) is a common site of pathogen replication. Many of these pathogens establish sexually transmitted infections (STls) that are a hidden epidemic of significant health and economic concern worldwide. Many STls, including HIV and Herpes simplex virus (HSV), lack curative therapies and would immensely benefit from preventive vaccination. Anti-HIV and HSV-2 vaccine trials that are solely focused on generating neutralizing antibodies have so far failed to provide significant protective benefits. There is a growing realization that an effective mucosal vaccine regimen should elicit both antibodies and T cells. Resident memory T cells (TRM), the dominant T cell population in the genital mucosa, represent a primary defense mechanism against intracellular pathogens. Contrary to circulating memory T cells, TRM establish permanent residence in their tissue of origin and do not routinely circulate via blood and lymph. Reductionist experiments in rodent and non-human primate models suggest a strong protective role of mucosal TRM located near the site of infection. Hence, establishing an abundant number of highly functional CD8 TRM in the FRT to mediate rapid pathogen clearance is a key long-term goal of many vaccination programs. However, achieving sufficient quantity and quality of mucosal TRM hinges on a detailed understanding of the differentiation and maintenance requirement of these cells. It has been recently recognized that the local environmental milieu is a significant contributor to TRM differentiation program and their long-term maintenance. Our preliminary data indicate a critical role of estrogen in impacting FRT TRM formation. The overall objective of this proposal is to interrogate the contributions of sex-hormone and the local microbiome in shaping the FRT TRM compartment. Under first aim, we will utilize reductionist mouse model based approaches to investigate the role CD8 T cell intrinsic estrogen signaling in establishment of FRT TRM. In the second aim, we will use germfree mice and microbiome depletion approaches to examine the influence of local microbiome on TRM formation and function. Identification of local factors that contribute to TRM differentiation and function will aid in developing methods to generate a robust T cell response in the reproductive mucosa.