Mechanisms of Protective Local Immunity in Human Female Reproductive Tract

描述（由申请人提供）：性传播疾病（STDs）的流行在全球范围内增加，造成严重的医疗和心理后果。尽管做出了重大努力，但旨在预防或治疗性传播感染（STIs），如艾滋病毒和2型单纯疱疹病毒（HSV-2）的疫苗开发在很大程度上是不成功的。阴道和子宫颈外的粘膜表面既是进入点，也是防止性传播病原体的屏障。组织定位记忆T细胞通过直接靶向感染细胞和从循环中招募记忆T细胞，在皮肤和粘膜中提供第一道防线。我们已经证明CD8 T细胞不仅浸润到感染部位，而且还长期存在于生殖器皮肤和粘膜中

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 CD8αα homodimer as a co-receptor instead of the heterodimeric CD8αß, which dominates blood circulating CD8 T cells. Surface expression of the CD8αα homodimer is also characteristic of intraepithelial lymphocytes (IEL) resident in the gut epithelium and mucosal associated invariant T cells (MAIT). CD8αα has been proposed to preserve high-affinity effector T cells for long-lived mucosal memory. Whether CD8αα 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 CD8αα 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, CD8αα and CD8αß 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.