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，涉及蜕膜和子宫内母体细胞之间的免疫串扰。 胎儿细胞。这种沟通在保护胎儿免受排斥方面发挥着重要作用。外柔内刚 滋养层细胞 (EVT) 是塑造母胎免疫微环境的关键胎儿细胞 (M-F) 接口。 EVT 在其上表达一组独特的主要组织相容性复合体 (MHC I) 分子 表面：经典 HLA-C 和非经典 HLA-E、-F 和 -G 分子。非常特殊的是，EVT 确实 不表达 HLA-A 和 HLA-B。 HLA-C、-E 和 -G 分子与以下机制相关： M-F 界面的免疫耐受性以及 HLA-F 是否具有类似的功能尚不清楚。 HLA-F 是 MHC I 分子在以下几个方面具有独特性： 1. HLA-F 以不止一种分子形式存在，具有 和 不含相关肽和 b2m； 2. HLA-F 结合非常长的肽，范围从 8聚体至20聚体以上； 3. 自然杀伤 (NK) 细胞上的抑制性和激活性受体可以 区分充满肽和缺乏肽的 HLA-F 分子。因此，提出以下建议是合乎逻辑的： HLA-F 在 M-F 免疫串扰中的作用涉及 EVT 上表达的 HLA-F 与 NK 之间的相互作用 蜕膜 NK 细胞上的受体。 EVT 上的 HLA-F 表达是最重要的这一知识强化了这一点。 NK 细胞在妊娠早期含量丰富，是母体免疫细胞中最大的群体。 怀孕前三个月的蜕膜。因此，为了了解 HLA-F 的功能 作为一种免疫调节分子，我们对肽结合有深入的了解至关重要 HLA-F 的特性以及肽调节与 NK 细胞受体相互作用的机制。这 R21 应用是一项早期研究，旨在填补我们对 HLA-F 知识中尚未解决的空白 免疫生物学。为了实现两个目标，我们建议研究 HLA-F 肽与以下疾病相关的独特景观： 专门的氨肽酶通常在细胞内产生 MHC I 免疫肽组，并解决 关键问题集中在为什么 HLA-F 呈现出长度特别长的肽、什么生化和 HLA-F 的结构特性支持长肽的结合，以及肽在调节中的作用是什么 HLA-F 与 NK 细胞相互作用。为此，我们将结合使用基于细胞的、生化的和结构的 接近。该项目完成后，我们将产生有关 HLA-F 的新知识，这将有助于 了解其在 EVT 上的表达以及与蜕膜 NK 细胞上受体的结合如何支持 妊娠早期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，这是 HLA-F 的一个特征 这里提出的建议对于激发管理和降低相关风险的新想法非常重要 这样的并发症。