HLA-F in maternal-fetal immune crosstalks

HLA-F 在母胎免疫串扰中的作用

• 批准号: 10667879
• 负责人: MARLENE BOUVIER
• 金额: $ 23.99万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-22 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10667879
• 关键词: Address; Aminopeptidase; Binding; Biochemical; Biological Assay; Blood; Cell Shape; Cells; Communication; Complex; Decidua; Endometrium; Ensure; Family; Fetus; First Pregnancy Trimester; HLA-A gene; HLA-B Antigens; HLA-C Antigens; Immune; Immune Tolerance; Immunobiology; Immunoglobulins; Immunologics; In Vitro; Invaded; Investigation; KIR3DS1; Knowledge; Length; Leukocytes; Major Histocompatibility Complex; Mass Spectrum Analysis; Maternal-Fetal Exchange; Maternally-Acquired Immunity; Molecular; NK cell receptor NKB1; Natural Killer Cells; Pathology; Peptides; Physiological Processes; Placenta; Play; Population; Pregnancy; Pregnancy Complications; Property; Receptor Cell; Risk; Role; Scheme; Spiral Artery of the Endometrium; Spontaneous abortion; Surface; Tissues; Uterus; Vascular remodeling; Villous; Work; X-Ray Crystallography; biophysical techniques; cell type; conformer; design; early pregnancy; fetal; fetus cell; healthy pregnancy; immunoregulation; implantation; infant death; killer inhibitory receptor; migration; pregnancy disorder; receptor; trophoblast; tumor-immune system interactions

ABSTRACT Pregnancy is a complex state that involves immune crosstalks between maternal cells in the decidua and fetal cells. This communication plays an important role in protecting the fetus from rejection. Extravillous trophoblasts (EVTs) are critical fetal cells that shape the immunological microenvironment at the maternal-fetal (M-F) interface. EVTs express a unique set of major histocompatibility complex (MHC I) molecules on their surfaces: the classical HLA-C and non-classical HLA-E, -F, and -G molecules. Quite exceptionally, EVTs do not express HLA-A and HLA-B. HLA-C, -E, and -G molecules have been associated with mechanisms of immune tolerance at the M-F interface, and whether HLA-F functions similarly is less well understood. HLA-F is unique among MHC I molecules in several ways: 1. HLA-F exists in more than one molecular form, with and without associated peptides and b2m; 2. HLA-F binds peptides that are unconventionally long, ranging from 8mers to more than 20mers; and 3. Inhibitory and activating receptors on natural killer (NK) cells can distinguish between peptide-filled and peptide-deficient HLA-F molecules. It is therefore logical to propose that a role for HLA-F in M-F immune crosstalks involves interactions between HLA-F expressed on EVTs and NK receptors on decidual NK cells. This is reinforced by the knowledge that HLA-F expression on EVTs is most abundant in early pregnancy, and that NK cells constitute the largest population of maternal immune cells in the decidua during the first trimester of pregnancy. Thus, to develop an understanding of how HLA-F functions as an immunoregulatory molecule, it is critical that we have a strong understanding of the peptide binding properties of HLA-F and the mechanisms by which peptides modulate interactions with NK cell receptors. This R21 application is an early-stage investigation that aims to fill unresolved gaps in our knowledge of HLA-F immunobiology. In two aims, we propose to examine the unique landscape of HLA-F peptides in relation to specialized aminopeptidases that normally generate MHC I immunopeptidomes inside cells, as well as address key questions centered on why HLA-F presents peptides of extraordinarily long lengths, what biochemical and structural properties of HLA-F support binding of long peptides, and what is the role of peptides in modulating HLA-F interaction with NK cells. For this, we will use a combination of cell-based, biochemical, and structural approaches. Upon completion of this project, we will have generated new knowledge on HLA-F that will help understand how its expression on EVTs and engagement with receptors on decidual NK cells, can support a critical regulatory role in immune crosstalks during the early stages of pregnancy. Given that pregnancy complications are often associated with a loss of immune tolerance mechanisms, a characterization of HLA-F as proposed here is important for stimulating new ideas in managing and decreasing the risks associated with such complications.

抽象的 怀孕是一个复杂的状态，涉及Decidua和 胎儿细胞。这种沟通在保护胎儿免于拒绝方面起着重要作用。奢侈 滋养细胞（EVT）是关键的胎儿细胞，可在母亲面上塑造免疫学微环境 （M-F）接口。 EVT在其上表达一组独特的主要组织相容性复合物（MHC I）分子 表面：经典的HLA-C和非经典HLA-E，-F和-G分子。相当异常，EVT确实 不是表达HLA-A和HLA-B。 HLA -C，-e和-g分子与机制有关 M-F界面的免疫耐受性以及HLA-F的功能是否类似地理解。 HLA-F是 MHC I分子在几种方面唯一：1。HLA-F以多种分子形式存在，带有和 没有相关的肽和B2M； 2。hla-f结合了不常见的肽，范围从 8mers到20多人；和3。抑制性和激活自然杀手（NK）细胞的受体可以 区分肽填充和缺乏肽的HLA-F分子。因此，提出 HLA-F在M-F免疫串扰中的作用涉及在EVT和NK上表达的HLA-F之间的相互作用 在decIDual NK细胞上的受体。这是由于HLA-F在EVT上表达最多的知识而加强了这一点 在怀孕初期，大量的NK细胞构成了母体免疫细胞中最大的群体 妊娠三个月期间的Decidua。因此，要了解HLA-F如何功能的理解 作为一种免疫调节分子，至关重要的是我们对肽结合有很强的了解 HLA-F的性质以及肽调节与NK细胞受体相互作用的机制。这 R21申请是一项早期调查，旨在填补我们对HLA-F的尚未解决的空白 免疫生物学。在两个目的中，我们建议研究与HLA-F肽的独特景观 通常会在细胞内部产生MHC I免疫肽的专门氨基肽酶，并且地址 关键问题集中在HLA-F为何提出非常长的肽，什么生化和 HLA-F支持长肽的结构特性，肽在调节中的作用是什么 HLA-F与NK细胞的相互作用。为此，我们将使用基于细胞的，生化和结构的组合 方法。该项目完成后，我们将获得有关HLA-F的新知识，这将有助于 了解其在EVT上的表达以及在决定性NK细胞上与受体的互动如何支持 在怀孕初期，在免疫串扰中的关键调节作用。鉴于怀孕 并发症通常与免疫耐受机制的丧失有关，HLA-F的表征 如这里提议的 这样的并发症。