The role of Chlamydia trachomatis specific HLA-E restricted CD8 T cell responses in clearance of infection

项目总结 沙眼衣原体(CT)感染仍然是最常见的细菌性性传播感染(STI) 全世界，每年报告的新CT感染人数超过1.2亿。在美国，非裔美国人和妇女 不成比例地受到CT感染的影响。尽管最近报告的CT病例超过150万例， 在美国，这可能是低估了，因为上述弱势群体在#年经历了不平等 获得常规医疗服务。由于许多生殖疾病，女性感染CT的负担更大 与这种感染相关的并发症。到目前为止，预防和控制努力并未显著减少。 CT感染率。此外，高达20%的感染者在一年内再次感染，这表明 短命的或不理想的免疫力。在小鼠模型和人体研究的背景下，我们和其他人 先前显示产生干扰素-γ的T细胞在清除衣原体和保护衣原体中的作用 再感染。然而，最近对人类的研究表明，CD8T细胞可能在CT感染中发挥作用，因为 井。CD8T细胞在感染细胞通过经典的MHC-1呈递的多肽的背景下识别病原体。 IA等位基因(在人类中，为HLA-A、B或C)或非经典的MHC-Ib等位基因(在人类中，为HLA-E)。前期工作 研究表明，人类白细胞抗原-E限制性CD8T细胞(HLA-E/CD8s)在免疫调节中发挥重要作用 几种细胞内的细菌病原体，如分枝杆菌和沙门氏菌。人类白细胞抗原E/CD8在人类免疫缺陷中的作用 CT感染与CT感染的清除有关，目前尚不清楚。之前两项检测CD8的人体研究 T细胞对CT的反应间接显示了受非经典的HLA-I等位基因限制的反应。然而， 这种限制的确切性质和这种细胞在疾病发病机制中的作用，因为它与清除有关 沙眼衣原体感染的定义不明确。由于人类白细胞抗原Ia和人类白细胞抗原Ib(即，人类白细胞抗原E)是普遍共表达的， 需要适当的分子工具和方法学来剖析CD8 T细胞的独特贡献 对通过这些等位基因中的每一个呈现的多肽做出反应。我们最近生成了HLA-E*01：01和 E*01：03特定的细胞资源，使我们能够识别HLA-E/CD8并评估它们在 CT感染的背景。具体来说，我们的初步数据显示，人类白细胞抗原E/CD8产生CD107a/干扰素-γ/肿瘤坏死因子- 在清除CT感染的妇女中优先检测到α。我们的总体假设是，人类白细胞抗原E受到限制 CD8T细胞在清除女性沙眼衣原体感染中将发挥重要作用。在目标1中，我们将确定 CT特异性的人类白细胞抗原E限制性CD8T细胞在女性CT感染清除中发挥作用。在目标2中，我们 将确定CT特异性的HLA-E限制性CD8 T细胞是否可以从CT天真的女性捐赠者中激发出来 目前或以前感染过CT。总而言之，我们完成的研究将证明生物相关性和 人类白细胞抗原-E限制性CD8 T细胞反应在清除CT感染中的功能及其直接应用 用于基于CT的预防性疫苗的免疫原选择。

PROJECT SUMMARY Chlamydia trachomatis (CT) infection remains the most prevalent bacterial sexually transmitted infection (STI) worldwide, with over 120 million new CT infections reported annually. In the US, African Americans and women are disproportionally affected by CT infection. Although over 1.5 million CT cases were recently reported in the US, this is likely an underestimation as the above-mentioned vulnerable population experiences inequities in access to routine healthcare. Women experience a greater burden of CT infection due to many reproductive complications associated with this infection. To date, prevention and control efforts have not significantly reduced CT infection rates. In addition, up to 20% of infected persons are reinfected within a year suggesting either a short lived or suboptimal immunity. In the context of both murine models and human studies, we and others have previously showed a role of IFN-γ-producing CD4+ T cells in chlamydia clearance and protection against reinfection. Recent studies in humans have however shown that CD8 T cells could play a role in CT infection as well. CD8 T cells recognize pathogens in the context of peptides presented by an infected cell via classical MHC- Ia alleles (in humans, HLA-A, B or C) or non-classical MHC-Ib alleles (in case of humans, HLA-E). Prior work has shown that HLA-E restricted CD8 T cells (HLA-E/CD8s) exert an important immune-regulatory role in control of several intracellular bacterial pathogens such as Mycobacterium and Salmonella. The role of HLA-E/CD8s in CT infection as it pertains to clearance of CT infection is unknown. Two previous human studies examining CD8 T cell responses to CT indirectly demonstrated responses restricted by non-classical HLA-I alleles. However, the precise nature of this restriction and the role of such cells in disease pathogenesis as it pertains to clearance of CT infection was not defined. Since HLA-Ia and HLA-Ib (i.e., HLA-E) are ubiquitously co-expressed, appropriate molecular tools and methodologies are needed to dissect the unique contributions of CD8 T cells responding to peptides presented via each of these alleles. We have recently generated HLA-E*01:01 and E*01:03 specific cellular resources that allowed us to identify HLA-E/CD8s and to assess their relevance in the context of CT infection. Specifically, our preliminary data shows that HLA-E/CD8s producing CD107a/IFN-γ/TNF- α are preferentially detected in women who clear CT infection. Our overall hypothesis is that HLA-E restricted CD8 T cells will play an important role in clearance of CT infection in women. In Aim 1, we will determine if CT-specific HLA-E restricted CD8 T cells play a role in the clearance of CT infection in women. In Aim 2, we will determine if CT-specific HLA-E restricted CD8 T cells can be primed from CT naïve female donors with no current or prior CT infection. In summary our completed studies will demonstrate the biological relevance and functionality of HLA-E restricted CD8 T cell response in clearance of CT infection and thus has direct applications for immunogen selection for a preventative CT based vaccine.