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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.

摘要胎盘和蜕膜分泌因子作为免疫调节因子的重要性需要进行调整，以适应遗传上不同的母亲和胎儿，血绒膜妊娠是公认的。半乳糖凝集素是具有细胞内和细胞外特性的凝集素家族。细胞外功能分泌的半乳凝素与N-乙酰基乳糖胺（LacNAc）结合并形成晶格在细胞表面和细胞之间的糖蛋白之间，促进过多的生物活性，包括调节适应性和先天性免疫应答。成员半乳糖凝集素家族的三个成员在碳水化合物特异性和亲和力方面表现出显著的差异，在不同的功能。最近，半乳糖凝集素-9（Gal-9），表达于母体胎儿- 界面，已被建议通过结合其受体在母体T细胞耐受性中发挥作用其中包括T细胞免疫球蛋白和含有粘蛋白结构域的-3（Tim-3）， CD44。另一方面，已经报道Gal-9诱导促炎性细胞因子的分泌。细胞因子。最近，我们发现妊娠特异性糖蛋白1（PSG 1），其由胎盘滋养层细胞分泌，随着妊娠的进行浓度增加，与Gal-9结合。PSG 1以高亲和力与Gal-9结合，并且相互作用是聚糖介导的。重要的是，在某些妊娠并发症中，PSG 1的浓度低于正常水平。包括先兆子痫先天性免疫系统的激活被认为有助于滋养层细胞在早期的蜕膜和分娩的入侵，但它也与不利的妊娠中期和妊娠晚期发生的妊娠结局。因此，在怀孕期间减少炎症的空间方面代表了一个复杂而重要的怀孕成功的过程。我们提出，新发现的Gal-9和 PSG 1有助于怀孕所需的免疫反应的质的差异除了先前确定的个别职能外，这两种蛋白质在免疫细胞的调节中起重要作用。因此我们建议进行以下具体目标：（1）分析天然和重组的结合 PSG 1与Gal-9的N-末端和C-末端碳水化合物识别结构域的结合。(2)确定 PSG 1和Gal-9或单个Gal-9 CRD对表型和单核细胞和蜕膜巨噬细胞分泌细胞因子。(3)确定 PSG 1和Gal-9单独和联合治疗对人CD 4 + T细胞的影响 CD 4 + FoxP 3 + T调节细胞的凋亡和频率。