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

• 批准号: 10302501
• 负责人: Gabriela S Dveksler
• 金额: $ 19.06万
• 依托单位: HENRY M. JACKSON FDN FOR THE ADV MIL/MED
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-18 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10302501
• 关键词: Accounting; Acute Graft Versus Host Disease; Adaptive Immune System; Address; Affect; Affinity; Allografting; Amino Acid Sequence; Apoptosis; Binding; Biochemical; Biological; Biological Assay; Biological Response Modifiers; Birth; Blood Circulation; C-terminal; CD4 Positive T Lymphocytes; CD44 gene; Carbohydrates; Cell surface; Cells; Colitis; Combined Modality Therapy; Complex; Decidua; Disease; Disease model; Enzyme-Linked Immunosorbent Assay; Etiology; Exhibits; FOXP3 gene; Family; Fetal Growth Retardation; Fetus; Frequencies; Galactose Binding Lectin; Glycoproteins; Goals; Habitual Abortion; Hematology; Human; IL2RA gene; Immune; Immune Tolerance; Immune response; Immune system; Immunoglobulins; Individual; Inflammation; Inflammatory; Innate Immune Response; Innate Immune System; Knowledge; Lead; Lectin; Ligands; Maternal-Fetal Exchange; Mediating; Molecular; Mothers; Mucins; Myeloid Cells; N-acetyllactosamine; N-terminal; Observational Study; Phenotype; Physiological; Placenta; Play; Polysaccharides; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Pregnancy loss; Pregnant Women; Process; Production; Proteins; Recombinants; Recurrence; Regulation; Regulatory T-Lymphocyte; Reporting; Research; Role; Second Pregnancy Trimester; Specificity; Surface Plasmon Resonance; T cell response; T-Lymphocyte; Testing; Therapeutic; Third Pregnancy Trimester; adaptive immune response; adverse pregnancy outcome; autoimmune arthritis; chemokine; cytokine; design; experimental study; extracellular; fetal; healthy pregnancy; immunomodulatory therapies; immunoregulation; improved; insight; macrophage; member; monocyte; novel therapeutic intervention; perinatal outcomes; pre-clinical; receptor; success; trophoblast

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 胎盘和蜕膜分泌因子作为免疫介质的重要性 需要进行调整以适应基因不同的母亲和胎儿 血绒妊娠是众所周知的。半乳糖凝集素是一类具有细胞内和 细胞外功能。分泌的半乳糖凝集素与 N-乙酰基乳糖胺 (LacNAc) 结合并形成晶格 细胞表面和细胞之间的糖蛋白之间，促进大量的 生物活性，包括适应性和先天免疫反应的调节。会员 半乳糖凝集素家族的成员在碳水化合物特异性和亲和力方面表现出显着差异 在不同的功能中。最近，半乳糖凝集素 9 (Gal-9) 在母胎中表达， 界面，已被认为通过与其受体结合在母体 T 细胞耐受中发挥作用 其中包括 T 细胞免疫球蛋白和 mucin-domain contains-3 (Tim-3) 和 CD44。另一方面，Gal-9 据报道可诱导促炎物质的分泌。 骨髓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，胎盘滋养层分泌的浓度不断增加， 与 Gal-9 结合。 PSG1 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 PSG1 的浓度低于正常值 包括先兆子痫。 已提出先天免疫系统的激活有助于滋养层 侵入早期蜕膜并导致分娩，但它也与不良反应有关 妊娠中期和晚期的妊娠结局。因此，时间 减少怀孕期间炎症的空间和空间方面代表了一个复杂而重要的问题 怀孕成功的过程。我们提出新发现的 Gal-9 和 PSG1 导致妊娠所需免疫反应的质的差异 成功以及除了之前确定的各自功能之外，之间的相互作用 这两种蛋白质在免疫细胞的调节中发挥着重要作用。因此我们 建议实现以下具体目标：（1）分析天然和重组体的结合 PSG1 连接到 Gal-9 的 N 端和 C 端碳水化合物识别域。 (2)确定 PSG1 和 Gal-9 或单个 Gal-9 CRD 对 单核细胞和蜕膜巨噬细胞的表型和细胞因子分泌。 (3)确定 PSG1 和 Gal-9 单独和联合治疗对人 CD4+ T 细胞的影响 CD4+ FoxP3+ T 调节细胞的凋亡和频率。