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

摘要 胎盘和蜕膜分泌因子作为免疫学介质的重要性 需要进行调整以适应基因不同的母亲和胎儿 绒毛膜妊娠是公认的。Galectins是一个凝集素家族，具有细胞内和 细胞外功能。分泌型Galectins与N-乙酰乳糖胺(LacNAc)结合形成晶格 在细胞表面和细胞之间的糖蛋白之间，促进过多的 生物活动，包括调节适应性免疫反应和先天免疫反应。成员 在碳水化合物专一性和亲和力方面表现出显著的差异 在不同的功能中。最近，在母体胎儿表达的Galectin-9(Galectin-9，Gal-9)- 界面被认为通过与其受体结合而在母体T细胞耐受中发挥作用 其中包括T细胞免疫球蛋白和含有-3的粘蛋白结构域(Tim-3)和 CD44。另一方面，据报道，Gal-9可以诱导促炎因子的分泌 髓系细胞产生的细胞因子。最近，我们发现妊娠特异性糖蛋白1(PSG1)， 随着妊娠的进展，胎盘滋养层细胞分泌的激素浓度不断增加， 与Gal-9结合。PSG1以高亲和力与Gal-9结合，这种相互作用是由多糖介导的。 重要的是，在一些妊娠并发症中，PSG1的浓度低于正常水平 包括先兆子痫。 天然免疫系统的激活被认为对滋养层细胞有贡献 侵袭早期蜕膜和分娩，然而，它也与不利的 妊娠结局发生在妊娠中期和晚期。因此，时间上的 而减少妊娠期间炎症的空间方面代表了一个复杂和必要的 怀孕成功的过程。我们认为，新发现的Gal-9和Gal-9之间的相互作用 PSG1导致了怀孕所需免疫反应的质的差异 成功和成功之间的相互作用，除了它们先前确定的个别功能之外 这两种蛋白在免疫细胞的调节中起着重要作用。因此我们 建议开展以下具体工作：(1)分析天然和重组蛋白的结合 PSG1到Gal-9的N-末端和C-末端碳水化合物识别结构域。(二)确定 PSG1、Gal-9或Gal-9 CRD单独及联合作用对血管内皮细胞生长的影响 单核细胞和蜕膜巨噬细胞的表型和细胞因子的分泌。(三)确定 PSG1和Gal-9单独及联合作用对人CD_4~+T细胞的影响 CD4+FoxP3+T细胞的凋亡率和频率。

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.