Impaired T cell immunity in the Elderly via enhanced N-glycosylation.

N-糖基化增强导致老年人 T 细胞免疫力受损。

• 批准号: 8975117
• 负责人: MICHAEL DEMETRIOU
• 金额: $ 46.14万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-12-15 至 2018-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8975117
• 关键词: Affect; Aged, 80 and over; Aging; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Antigens; Asparagine; Autoimmunity; Binding; Carbohydrates; Cell Differentiation process; Cell surface; Cells; Complex; Cytotoxic T-Lymphocyte-Associated Protein 4; Down-Regulation; Elderly; Endocytosis; Enzymes; Funding; Galactose Binding Lectin; Genetic; Genome; Golgi Apparatus; Growth Factor Receptors; Health; Human; Immune System Diseases; Immune response; Immunity; Immunization; In Vitro; Infection; Inflammatory; Membrane Glycoproteins; Metabolic; Metabolic Control; Molecular; Morbidity - disease rate; Mus; Pathway interactions; Phenotype; Polysaccharides; Predisposition; Protein Glycosylation; Proteins; Regulation; Risk; Serum; Signal Transduction; Supplementation; Surface; T cell response; T memory cell; T-Cell Receptor; T-Lymphocyte; T-Lymphocyte Subsets; Therapeutic; Transforming Growth Factors; age related; aged; cell growth; glycosylation; immune function; in vivo; inhibitor/antagonist; link protein; mortality; receptor; response; small molecule; sugar

DESCRIPTION (provided by applicant): Impaired T cell immunity and response to infection and immunization is a common feature in the elderly. We have previously shown that Asparagine (N) - linked protein glycosylation serves as a critical negative regulator of T cell immunity in both mice and humans. Virtually all cell surface and secreted proteins in animal cells are modified by the addition of complex carbohydrates in the ER/Golgi secretory pathway, providing molecular information not encoded in the genome. The branching and number of N-glycans per protein molecule cooperate to regulate binding to galectins, forming a molecular lattice that controls the distribution, clustering and endocytosis of surface glycoproteins in a predictable manner to affect cell growth and differentiation. Genetic and metabolic control of N-glyan branching negatively regulates T cell receptor clustering/signaling, enhances surface retention of the anti-inflammatory receptors Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) and Transforming Growth Factor - ¿ receptor (T¿R) and inhibits pro-inflammatory TH1 and TH17 while promoting anti-inflammatory TH2 and induced T regulatory cell (iTreg) differentiation. Increasing N-glycan branching in T cells in vitro and in vivo by metabolically increasing substrate supply to Golgi enzymes via supplementation with the simple sugar N-acetylglucosamine (GlcNAc) suppresses T cell growth, enhances CTLA-4 and TGF-¿RI/II surface expression, blocks TH1/TH17 differentiation and inhibits autoimmunity. Preliminary analysis suggests aging in humans and mice is associated with increases in serum GlcNAc levels and N-glycan branching in T cells, including na¿ve, central and effector memory T cells. Indeed, hypo-proliferative in vitro responses in aged mouse and human T cells is rescued by down-regulating N-glycan branching using a small molecule Golgi inhibitor. We hypothesize that age-dependent increases in N-glycan branching significantly contributes to impaired T cell immunity and hypo-responsiveness to infection/immunization in the elderly. To confirm and expand on this hypothesis, the following aims are proposed. Aim 1 will confirm increased N-glycan branching in human T cell subsets of the elderly. Aim 2 will confirm that genetic and small molecule inhibition of N-glycan branching rejuvenates T cell responses in the elderly. Aim 3 examines the mechanism for age dependent increases in N-glycan branching, examining both genetic and metabolic regulation. Positive results will suggest down-regulation of N-glycan branching as a therapeutic strategy to rejuvenate T cell responses in the elderly.

描述（由适用提供）：T细胞免疫学受损以及对感染和免疫学的反应是古老的特征。我们先前已经表明，天冬酰胺（N）连接的蛋白质糖基化是小鼠和人类T细胞免疫学的关键阴性调节剂。实际上，通过在ER/Golgi秘书途径中添加复杂的碳水化合物来改变动物细胞中的所有细胞表面和分泌的蛋白质，从而提供了未在基因组中编码的分子信息。每个蛋白质分子的N-聚糖的分支和数量合作以调节与甘叶蛋白的结合，形成了一种分子晶格，以可预测的方式控制表面糖蛋白的分布，聚类和内吞作用，以影响细胞生长和分化。 N-Glyan分支的遗传和代谢控制负面调节T细胞受体聚类/信号传导，增强了抗炎受体的表面保留抗炎受体的细胞毒性T-淋巴细胞抗原4（CTLA-4）（CTLA-4）的表面保留，并通过在V型细胞中促进T细胞在V型中增加批量生产，从而增加细胞的含量，从而增强T细胞的构元，从而增加VIL的促进量。补充简单的糖N-乙酰葡萄糖（GLCNAC）可抑制T细胞的生长，增强CTLA-4和TGF-€ri/II表面表达，阻止TH1/TH17分化并抑制自身免疫性。初步分析表明，人类和小鼠的衰老与T细胞（包括NAâVE，中央和效应子记忆T细胞）的血清GlcNAC水平和N-聚糖分支的增加有关。实际上，通过使用小分子高尔基抑制剂下调N-聚糖分支来挽救老年小鼠和人T细胞的体外反应性不足。我们假设N-聚糖分支的年龄依赖性增加显着导致T细胞免疫学受损和对老年人感染/免疫的反应性低。为了确认和扩展这一假设，提出了以下目标。 AIM 1将确认在较早的人类T细胞子集中增加N-聚糖分支。 AIM 2将证实遗传和小分子对N-聚糖分支的抑制会使T细胞反应恢复活力。 AIM 3考试N-聚糖分支的年龄依赖性增加的机制，研究了遗传和代谢调节。积极的结果将表明N-聚糖分支的下调是一种治疗策略，以使T细胞反应恢复原状。