HLA-F in maternal-fetal immune crosstalks

摘要 妊娠是一个复杂的状态，涉及蜕膜中母体细胞之间的免疫串扰， 胎儿细胞这种交流在保护胎儿免受排斥方面起着重要作用。绒毛外 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。非常例外的是，EVT 不表达HLA-A和HLA-B。HLA-C、-E和-G分子与人类免疫缺陷的机制有关。 M-F界面的免疫耐受性，以及HLA-F是否具有类似的功能还不太清楚。HLA-F是 在MHC I分子中以几种方式独特：1. HLA-F以一种以上的分子形式存在， 没有相关肽和b2 m; 2. HLA-F结合的肽是非常规的长，范围从 8聚体至大于20聚体;和3.自然杀伤（NK）细胞上的抑制性和激活性受体可以 区分肽填充的和肽缺陷的HLA-F分子。因此，合乎逻辑的建议是， HLA-F在M-F免疫串扰中的作用涉及EVT和NK上表达的HLA-F之间的相互作用 蜕膜NK细胞上的受体。这一点得到了以下知识的加强，即EVT上的HLA-F表达是最重要的。 NK细胞在妊娠早期大量存在，并且NK细胞构成了妊娠早期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， 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的认识中尚未解决的空白 免疫生物学在两个目标中，我们建议检查HLA-F肽与以下因素相关的独特景观： 专门的氨基肽酶，通常在细胞内产生MHC I免疫肽，以及地址 关键的问题集中在为什么HLA-F提出的肽非常长的长度，什么生化和 HLA-F的结构特性支持长肽的结合，肽在调节 HLA-F与NK细胞的相互作用。为此，我们将使用基于细胞的，生物化学的和结构的组合。 方法。在这个项目完成后，我们将产生新的知识HLA-F，这将有助于 了解它在EVT上的表达以及与蜕膜NK细胞上的受体的结合如何支持 在怀孕早期免疫串扰中起关键调节作用。鉴于怀孕 并发症通常与免疫耐受机制的丧失有关，免疫耐受机制是HLA-F的特征， 对于激发管理和减少与以下方面相关的风险的新想法非常重要： 如此复杂。

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.