HLA-F in maternal-fetal immune crosstalks

摘要 怀孕是一种复杂的状态，它涉及蜕膜中的母体细胞和 胎儿细胞。这种沟通在保护胎儿免受排斥方面起着重要作用。绒毛外 滋养层细胞是形成母婴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：经典的人类白细胞抗原-C和非经典的人类白细胞抗原-E、-F和-G分子。非常例外的是，EVT做到了 不表达人类白细胞抗原A和B。人类白细胞抗原-C、-E和-G分子已被认为与 M-F界面的免疫耐受，以及人类白细胞抗原-F是否具有相似的功能还不是很清楚。HL-F IS 在MHC I分子中在几个方面是独一无二的：1.HL A-F以多种分子形式存在，具有和 没有相关的多肽和B2M；2.HL A-F结合非常规长度的多肽，范围从 抑制和激活自然杀伤(NK)细胞上的受体可以 区分充满多肽和缺乏多肽的人类白细胞抗原-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细胞之间的相互作用 蜕膜NK细胞上的受体这一点得到了EVT上人类白细胞抗原-F表达最多的知识的支持 在怀孕早期大量存在，NK细胞构成了#年最大的母体免疫细胞群。 妊娠前三个月的蜕膜因此，为了加深对人类白细胞抗原F功能的理解 作为一种免疫调节分子，我们对多肽结合有一个深刻的了解是至关重要的 人类白细胞抗原F的特性及其调节与NK细胞受体相互作用的机制。这 R21的应用是一项早期研究，旨在填补我们对人类白细胞抗原F的认识中尚未解决的空白 免疫生物学。在两个目标中，我们建议研究人类白细胞抗原-F多肽的独特景观与 特殊的氨基肽酶，通常在细胞内产生MHC I免疫多肽，以及地址 关键问题集中在为什么HLA-F呈现超长的多肽，哪些生化和 人类白细胞抗原-F的结构特性支持长肽的结合，以及多肽在调节中的作用 HLA-F与NK细胞的相互作用。为此，我们将使用基于细胞的、生化的和结构的组合 接近了。在这个项目完成后，我们将产生关于人类白细胞抗原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细胞上的受体的接触如何支持 在怀孕早期免疫串扰中的关键调节作用。考虑到那次怀孕 并发症往往与免疫耐受机制的丧失有关，这是人类白细胞抗原F的特征 对于激发管理和降低与以下各项相关的风险的新想法非常重要 如此复杂的情况。

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.