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Analysis of vascular Galectin-9 as an immunomodulator of B-cell activity

血管 Galectin-9 作为 B 细胞活性免疫调节剂的分析

基本信息

批准号：
9981626
负责人：
CHARLES J DIMITROFF
金额：
$ 20.47万
依托单位：
FLORIDA INTERNATIONAL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-15 至 2021-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9981626
关键词：
Adhesions Adhesives Antibodies Antibody Formation Antibody Response Antigens Attenuated Attenuated Vaccines Autoimmune Diseases Automobile Driving B Cell Proliferation B-Cell Activation B-Lymphocyte Subsets B-Lymphocytes Binding Biological Assay Biology Blood Vessels CD22 gene Carbohydrates Cartoons Cell Adhesion Cell Adhesion Molecules Cell Communication Cell model Cell surface Cells Data Development Endothelial Cells Endothelium Foundations Galactose Binding Lectin Galactosides Genes Goals Grant High Endothelial Venule Homeostasis Homing Human Immune Immune response Immunity Immunology Immunomodulators In Situ Infection Inhibition of Cell Proliferation Investigation Knowledge Laboratories Lead Lectin Leukocytes Ligands Lupus Mediator of activation protein Memory Memory B-Lymphocyte Methods Modeling Molecular Mus Mutant Strains Mice N-acetyllactosamine PTPN6 gene Peripheral Physiological Plasma Cells Polysaccharides Positioning Attribute Proteins Protocols documentation Publishing Receptors, Antigen, B-Cell Regulation Role Signal Transduction Structure Structure of germinal center of lymph node Supporting Cell Therapeutic Tissues Tonsil Vaccination Vascular Endothelial Cell blood group cytokine experience high risk immunoregulation in vivo innovation insight lymph nodes lymphoid organ mouse model novel novel therapeutics peripheral tolerance recruit secondary lymphoid organ therapy design transcriptome sequencing

项目摘要

PROJECT ABSTRACT Development of effective antibody (Ab) responses is critically dependent on the recruitment of naïve B cells into secondary lymphoid organs and, upon antigen activation, their coordinated differentiation into germinal center (GC) B cells to memory B cells and Ab-producing plasma cells. Knowing which mechanistic factors control B cell subset transition with the therapeutic goal of Ab-boosting or -attenuating activity, however, is still poorly understood. Exciting new published data from our laboratory highlight striking differences in the glycomic signatures of human naïve, GC and memory B cell subsets featured by either i-linear or I-branched poly-N-acetyllactosamines (poly-LacNAcs). Whereas GC B cells express mainly I-branched poly-LacNAcs, naïve/memory B cells display principally i-linear poly-LacNAcs, which enable robust binding to immuno- modulator, galectin (Gal)-9. Gal-9-binding causes downstream inhibition of cell proliferation, activation and signaling related to BCR-engagement while, interestingly, evoking a pro-survival activity. Given the selective Gal-9-binding to naive/memory B cells, we speculate that Gal-9 serves as a physiologic “tuner” of peripheral B cell activation and B cell reactivity. Other key data on the distribution of Gal-9 in “reactive” lymph node (LN)- like tonsil tissue reveal that, while naïve B cells express endogenous Gal-9, Gal-9 expression is strongest on high endothelial venules (HEV). Since HEVs initiate adhesive contact with circulating naïve/memory B cells and are densely packed in the cortex adjacent to B cell follicles, HEVs are strategically poised to elicit Gal-9- dependent adhesion/regulation. The spatial, cellular and functional control of Gal-9 on B cells in lymphoid organs is still unknown and a major gap in the field of galectin immunology. Our guiding hypothesis is that Gal- 9 on HEV can bind circulating naïve/memory B cells and help recruit them into LNs as well as transmit regulatory signals as B cells traverse the endothelium and enter B cell follicles. In this exploratory proposal, we will examine the function of human endothelial cell (EC)-derived Gal-9 on human naïve B cell adhesion and immunoregulation and will assay for B cell homing to peripheral LNs in the presence/absence of Gal-9. The Specific Aims are: 1.) To study Gal-9-dependent vascular EC – B cell adhesive interactions and 2.) To analyze immunoregulatory effects of Gal-9 expressed by cytokine-activated human ECs on human naïve B cells. We will employ our unique experience and innovative primary human cell models, adhesion assays, mutant mice, gene editing methods to study whether Gal-9 on ECs supports naïve B cell adhesion, LN-homing as well as trigger immunoregulatory activity. These exploratory studies directly challenge current dogma that galectins largely function as immunoregulators, offering an alternative role for Gal-9 in facilitating B cell-EC adhesion, LN-homing and in situ peripheral control of B cell activity. Importantly, our findings will reveal novel targets for modulating B cell immunity and provide necessary data for a grant larger in scope.

项目摘要