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.

摘要