Role of epididymal macrophages and dendritic cells in male reproductive function

附睾巨噬细胞和树突状细胞在男性生殖功能中的作用

• 批准号: 9274090
• 负责人: SYLVIE BRETON
• 金额: $ 34.88万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-12 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9274090
• 关键词: Ablation; Address; Affect; Antigen Presentation; Antigen-Presenting Cells; Antigens; Apical; Autoimmune Responses; Autoimmunity; Biological Assay; Biological Response Modifiers; Blood; Blood capillaries; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell Communication; Cells; Circulatory Process; Data; Dendrites; Dendritic Cells; Development; Diphtheria Toxin; Duct (organ) structure; Environment; Epididymis; Epithelial Cells; Epithelium; Equilibrium; FOXP3 gene; Family; Fenestrated Capillary; Fertility; Flow Cytometry; Funding; Goals; Image Cytometry; Imaging Techniques; Immune; Immune Tolerance; Immune response; Immunologic Contraception; Immunologic Techniques; Immunologics; In Vitro; Infertility; Inflammation; Injection of therapeutic agent; Laboratory Study; Laser Scanning Confocal Microscopy; Lymphocyte; Maintenance; Male Contraceptive Agents; Male Infertility; Mediating; Microinjections; Molecular Profiling; Mononuclear; Mucous Membrane; Mus; Names; Ovalbumin; Pathogenicity; Phagocytes; Phenotype; Play; Population; Population Heterogeneity; Positioning Attribute; Procedures; Process; Public Health; Regulatory T-Lymphocyte; Reproductive Physiology; Role; Sampling; Side; Sperm Maturation; Spermatogenic Cell; Surveys; T cell response; T-Lymphocyte; Testing; Testis; Tight Junctions; Transgenic Mice; Tube; Vascular blood supply; Work; antigen processing; base; cancer cell; capillary; cell motility; immune activation; immunoregulation; in vivo; intraepithelial; intravital imaging; intravital microscopy; macrophage; male; microorganism; microscopic imaging; mouse model; negative affect; novel; oral tolerance; pathogen; prevent; public health relevance; reproductive function; sperm cell; sperm quality; uptake; zygote

 DESCRIPTION (provided by applicant): Sperm acquire motility and the ability to fertilize and egg during their transit in the epididymis; post testicular sperm maturation and storage involve mechanisms mediated by the epididymal mucosa. One of the most intriguing and understudied aspects of male reproductive physiology is the ability of the excurrent duct to prevent the development of autoimmune responses against millions of autoantigenic spermatogenic cells and mature spermatozoa, meanwhile initiating very efficient immune responses against pathogenic microorganisms. The present application is focused on the role of macrophages (MΦ) and dendritic cells (DCs) in establishing the protective environment in which spermatozoa mature and are stored. MΦ and DCs are two closely related and extremely versatile families of cells that play critical roles in the initiation and regulation of immune responses. We have previously shown that the epididymis is populated by a dense and heterogeneous network of mononuclear phagocytes (MPs) expressing MΦ and DC markers; in the proximal epididymis, they establish intimate interactions with epididymal epithelial cells and are part of the blood- epididymis barrier. Therefore, they are strategically positioned to play a major role in the contro of male reproductive function. We hypothesize that MΦ and DCs cooperate to survey both sides of the blood- epididymis barrier to regulate the balance between immune tolerance and inflammation in the post-testicular environment. In Specific Aim 1, we characterize luminal antigen uptake and elucidate the mechanisms underlying tolerance to sperm antigens via the induction of a specific subset of regulatory T lymphocytes (Tregs). In Specific Aim 2, we will determine how MΦ and DCs prevent circulating pathogens from affecting spermatozoa by surveying local capillaries. Both aims will rely on the use of state-of-the-art microscopy imaging procedures (3D laser scanning confocal microscopy and two-photo intravital microscopy), transgenic mouse models, and immunological techniques (e.g. flow cytometry analysis, cross-talk assays to characterize MPs and T cell interactions) rarely used in reproductive physiology. The ultimate goal of this project is to provide new frameworks for the treatment of male immunological infertility (a major public health issue) and, conversely, for the control of male fertility via immunocontraception.

 描述(申请人提供)：精子获得运动和受精和卵子的能力在他们在附睾处的运输过程中；睾丸后的精子成熟和储存涉及由附睾粘膜调节的机制。男性生殖生理学最有趣和最未被研究的方面之一是流出道的能力，它能阻止对数百万自身抗原生精细胞和成熟精子的自身免疫反应的发展，同时对病原微生物启动非常有效的免疫反应。目前的应用主要集中在巨噬细胞(MΦ)和树突状细胞(DC)在建立精子成熟和储存的保护环境中的作用。树突状细胞(MΦ)和树突状细胞(DC)是两个密切相关且功能极为广泛的细胞家族，它们在免疫应答的启动和调节中起着关键作用。我们先前已经证明，附睾由表达M-Φ和DC标记的单核巨噬细胞(MPS)组成的密集而异质的网络填充；在附睾近端，它们与附睾上皮细胞建立密切的相互作用，是血-附睾屏障的一部分。因此，它们在控制雄性生殖功能方面具有重要的战略地位。我们假设MΦ和DC合作调查血液-附睾屏障的两侧，以调节睾丸后环境中免疫耐受和炎症之间的平衡。在特定的目标1中，我们描述了管腔抗原摄取的特征，并阐明了通过诱导特定的调节性T淋巴细胞亚群(Tregs)来对精子抗原耐受的机制。在具体目标2中，我们将通过调查局部毛细血管来确定MΦ和DC如何防止循环病原体影响精子。这两个目标都将依赖于生殖生理学中很少使用的最先进的显微成像程序(3D激光扫描共聚焦显微镜和双照片活体显微镜)、转基因小鼠模型和免疫学技术(例如，流式细胞仪分析、串扰分析以表征MPS和T细胞相互作用)。该项目的最终目标是为治疗男性免疫性不育症(一个重大公共卫生问题)提供新的框架，反之，为通过免疫避孕控制男性生育提供新的框架。