Interaction of Galectin-9 and Pregnancy-Specific Glycoprotein 1 in the Regulation of Cells of the Innate and Adaptive Immune System

Galectin-9 和妊娠特异性糖蛋白 1 在先天性和适应性免疫系统细胞调节中的相互作用

基本信息

批准号：
10434937
负责人：
Gabriela S Dveksler
金额：
$ 22.87万
依托单位：
HENRY M. JACKSON FDN FOR THE ADV MIL/MED
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-18 至 2025-05-31
项目状态：
未结题

项目摘要

ABSTRACT The importance of placental and decidual secreted factors as mediators of the immunological adjustments needed to accommodate the genetically different mother and fetus during hemochorial pregnancies is well recognized. Galectins are a family of lectins with intracellular and extracellular functions. Secreted galectins bind to N-acetyllactosamine (LacNAc) and form lattices between glycoproteins on the surface of cells and between cells, promoting a plethora of biological activities including regulation of the adaptive and innate immune response. Members of the galectin family exhibit notable differences in carbohydrate specificity and affinity resulting in different functions. Recently, Galectin-9 (Gal-9), which is expressed at the maternal fetal- interface, has been suggested to play a role in maternal T-cell tolerance by binding to its receptors which include among others T cell immunoglobulin and mucin-domain containing-3 (Tim-3) and CD44. On the other hand, Gal-9 has been reported to induce the secretion of pro-inflammatory cytokines by myeloid cells. Recently, we found that Pregnancy-specific glycoprotein 1(PSG1), which is secreted by placental trophoblasts at increasing concentration as pregnancy progresses, binds to Gal-9. PSG1 binds to Gal-9 with high affinity and the interaction is glycan-mediated. Importantly, the concentration of PSG1 is lower than normal in some pregnancy complications including pre-eclampsia. Activation of the innate immune system has been proposed to contribute to trophoblast invasion in the early decidua and to parturition, however it is also associated with adverse pregnancy outcomes when it occurs in the second and third trimesters. Therefore, the temporal and spatial aspects of reducing inflammation during pregnancy represent a complex and essential process for pregnancy success. We propose that the newly found interaction between Gal-9 and PSG1 contributes to the qualitative differences in the immune response required for pregnancy success and that besides their previously identified individual functions, the interplay between these two proteins plays an important role in the modulation of immune cells. Therefore we propose to carry out the following Specific Aims: (1) Analyze the binding of native and recombinant PSG1 to the N-terminal and C-terminal carbohydrate recognition domains of Gal-9. (2) Determine the individual and combined effects of PSG1 and Gal-9 or the individual Gal-9 CRDs on the phenotype and secretion of cytokines by monocytes and decidual macrophages. (3) Determine the effect of individual and combined treatment of PSG1 and Gal-9 in human CD4+ T-cell apoptosis and frequency of CD4+ FoxP3+ T-regulatory cells.

抽象的作为免疫学的介体的胎盘和决定型分泌因素的重要性需要调整以适应遗传上不同的母亲和胎儿良好的妊娠知名度很高。 letectin是一个具有细胞内和的凝集素家族细胞外功能。分泌的半乳肠蛋白结合N-乙酰乳糖胺（LACNAC）并形成晶格在细胞表面和细胞之间的糖蛋白之间，促进了很多生物学活动，包括调节适应性和先天免疫反应。成员甲状腺素家族的碳水化合物特异性和亲和力的差异很明显在不同的功能中。最近，Galectin-9（GAL-9），在母亲胎儿表达界面已被建议通过结合其受体在母体T细胞的耐受性中发挥作用其中包括T细胞免疫球蛋白和含有-3（TIM-3）和 CD44。另一方面，据报道GAL-9诱导促炎的分泌髓样细胞的细胞因子。最近，我们发现妊娠特异性糖蛋白1（PSG1），随着妊娠的进展，胎盘滋养细胞分泌，浓度越来越大，结合Gal-9。 PSG1与高亲和力的GAL-9结合，相互作用是聚糖介导的。重要的是，在某些妊娠并发症中，PSG1的浓度低于正常包括先兆子痫。已经提出了先天免疫系统的激活，以促进滋养细胞在早期的deciDua和分娩中的入侵，但也与不利有关妊娠结局发生在第二和第三个三物质中。因此，时间减少怀孕期间炎症的空间方面代表了一个复杂而必不可少的怀孕成功的过程。我们建议新发现的Gal-9和 PSG1导致怀孕所需的免疫反应的定性差异成功，除了他们先前确定的个人功能外，这两种蛋白质在免疫细胞的调节中起重要作用。因此我们建议执行以下特定目的：（1）分析天然和重组的结合 pSG1至GAL-9的N末端和C末端碳水化合物识别域。（2）确定 PSG1和GAL-9的个体和组合效应或单个GAL-9 CRD对单核细胞和决结巨噬细胞对细胞因子的表型和分泌。（3）确定 PSG1和GAL-9在人CD4+ T细胞中的单个和联合处理的影响 CD4+ FOXP3+ T调节细胞的凋亡和频率。