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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

基本信息

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
项目类别：
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

项目摘要

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.