Mechanisms of Protective Local Immunity in Human Female Reproductive Tract

人类女性生殖道保护性局部免疫机制

基本信息

批准号：
8705241
负责人：
Jia Zhu
金额：
$ 32.1万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-03-05 至 2019-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8705241
关键词：
Address Affinity Anatomy Antibodies Antigens Biopsy Blood Blood Circulation CD4 Positive T Lymphocytes CD8B1 gene Cell physiology Cells Cellular Immunity Cervical Cervix Uteri Characteristics Collaborations Confocal Microscopy Containment Cues Disease Down-Regulation Epithelial Cells Epithelium Exhibits Exocervix Female Future Genital system Goals HIV Healed High-Throughput Nucleotide Sequencing Human Human Herpesvirus 2 Human Papilloma Virus Vaccine Immune Immune response Immunity Immunofluorescence Microscopy Immunologic Surveillance Immunotherapeutic agent Individual Infection Intervention Investigation Knowledge Langerhans cell Lesion Life Location Lymphocyte Mediating Medical Memory Methods Mucosal Immune Responses Mucosal Immunity Mucous Membrane Nature Patients Peripheral Play Population Prevalence Public Health Publishing Punch Biopsy Recruitment Activity Regulation Residencies Role Sampling Sexually Transmitted Diseases Site Skin Spatial Distribution Surface T memory cell T-Cell Receptor T-Lymphocyte Techniques Technology Time Tissues Vaccination Vaccine Design Vaccines Vagina Viral Virus Vulva Work base cell type chemokine receptor design gastrointestinal epithelium genital herpes healing human female immune function intraepithelial laser capture microdissection memory CD4 T lymphocyte novel pathogen prevent prophylactic psychologic public health relevance receptor receptor expression reproductive residence response self-renewal trafficking transcription factor transmission process vaccine development

项目摘要

DESCRIPTION (provided by applicant): The prevalence of sexually transmitted diseases (STDs) has increased globally with severe medical and psychological consequences. Despite major efforts, vaccine development aiming to either prevent or treat sexually transmitted infections (STIs), such as HIV and herpes simplex virus type 2 (HSV-2), has been largely unsuccessful. The mucosal surface of the vagina and ectocervix serves as both the point of entry as well as a barrier against sexually transmitted pathogens. Tissue-localized memory T cells provide a first line of defense in the skin and mucosa, by targeting infected cells directly and also by recruiting memory T cells from the circulation. We have shown that CD8 T cells not only infiltrate to the site of infection, but also persist in genital skin and mucosa for prolonged time periods after viral clearance. Our recently published work (Nature, 2013) indicates that CD8 T cells resident in human genital skin post healing of HSV-2 genital lesions express the CD8?? homodimer as a co-receptor instead of the heterodimeric CD8??, which dominates blood circulating CD8 T cells. Surface expression of the CD8?? homodimer is also characteristic of intraepithelial lymphocytes (IEL) resident in the gut epithelium and mucosal associated invariant T cells (MAIT). CD8?? has been proposed to preserve high-affinity effector T cells for long-lived mucosal memory. Whether CD8?? expression is a general mechanism for tissue resident memory in the human periphery is currently unclear. Here, we propose to investigate the immunological relevance of CD8?? T cells in the human female reproductive tract (FRT) using biopsies of vulva, vagina and ectocervical tissue, as well as the residency status of CD4 T cells. The overall goal of this proposal is to define the resident statuses of memory CD8 and CD4 T cells in FRT tissue compartments and to determine the mechanisms underlining their local retention, function and self- renewal capability. Using a combined approach of cell-type-specific laser capture microdissection (LCM), transcriptional profiling, high-throughput sequencing technology and multicolor confocal microscopy, we aim to 1) define the spatial dynamics of CD4, CD8?? and CD8?? T cells in the vulva, vagina and cervix; 2) determine the mechanism of tissue retention and function of memory T cells resident in human FRT; and 3) define microenvironmental cues promoting local proliferation of resident T cells. We believe a thorough investigation of cellular immunity in human FRT will broaden our knowledge of tissue resident immunity at the anatomical site of STI acquisition and transmission. These studies can then directly inform design of future vaccines and immunotherapeutic approaches that elicit tissue resident immune response with the hope of effectively protecting against STIs.

描述（由申请人提供）：性传播疾病（STD）的流行在全球范围内有所增加，带来了严重的医疗和心理后果。尽管做出了巨大努力，旨在预防或治疗性传播感染 (STI)（例如 HIV 和 2 型单纯疱疹病毒 (HSV-2)）的疫苗开发基本上并不成功。阴道和子宫颈外部的粘膜表面既是进入点，也是抵抗性传播病原体的屏障。组织局部记忆 T 细胞通过直接靶向受感染的细胞以及从循环中招募记忆 T 细胞，为皮肤和粘膜提供第一道防线。我们已经证明，CD8 T 细胞不仅可以浸润到感染部位，而且可以长期存在于生殖器皮肤和粘膜中。病毒清除后的时间段。我们最近发表的工作（《自然》，2013）表明，HSV-2 生殖器病变愈合后，驻留在人类生殖器皮肤中的 CD8 T 细胞表达 CD8??同型二聚体作为辅助受体，而不是异二聚体 CD8??，后者主导血液循环 CD8 T 细胞。 CD8的表面表达？？同二聚体也是驻留在肠上皮和粘膜相关不变 T 细胞 (MAIT) 中的上皮内淋巴细胞 (IEL) 的特征。 CD8？？已提出保留高亲和力效应 T 细胞以获得长寿命的粘膜记忆。是否CD8？？表达是人类外周组织驻留记忆的一般机制目前尚不清楚。在这里，我们建议研究CD8??的免疫学相关性。使用外阴、阴道和宫颈外组织活检来检测人类女性生殖道 (FRT) 中的 T 细胞，以及 CD4 T 细胞的驻留状态。该提案的总体目标是确定 FRT 组织区室中记忆 CD8 和 CD4 T 细胞的驻留状态，并确定强调其局部保留、功能和自我更新能力的机制。使用细胞类型特异性激光捕获显微切割 (LCM)、转录分析、高通量测序技术和多色共聚焦显微镜的组合方法，我们的目标是 1) 定义 CD4、CD8?? 的空间动力学？还有CD8？？外阴、阴道和子宫颈中的 T 细胞； 2）确定人类FRT中记忆T细胞的组织保留和功能机制； 3) 确定促进驻留 T 细胞局部增殖的微环境线索。我们相信，对人类 FRT 中细胞免疫的彻底研究将拓宽我们对 STI 获取和传播解剖部位的组织驻留免疫的了解。这些研究可以直接为未来疫苗和免疫治疗方法的设计提供信息，从而引发组织驻留免疫反应，以期有效预防性传播感染。