Galectin-1 regulation of T cell activation and tolerance

Galectin-1 对 T 细胞活化和耐受的调节

• 批准号: 6820004
• 负责人: M CARRIE MICELI
• 金额: $ 38.13万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-06-15 至 2007-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6820004
• 关键词: Galectin; regulation; cell; activation; tolerance

EXCEED THE SPACE PROVIDED. This proposal represents a series of studies designed to assess a potential role for endogenous galectin-1 in regulating T cell development, activation, and tolerance induction. The rationale for the proposed experiments stems from our studies defining galectin-1 as novel T cell regulator, capable of tuning TCR signals to selectively modulate functional outcome. Through a unique molecular mechanism involving reorganization of T cell glycoproteins within the T cell synapse, we propose that galectin-1 opposes costimulator-induced lipid raft recruitment to the synapse and processive and sustained TCR signal transduction. Our preliminary findings predict that endogenous galectin-1 might function in setting TCR signaling thresholds during T cell development and in preventing T cell hyper-activity and autoimmunity. Galectin-1 is expressed abundantly throughout the thymus and can cooperate with TCR engagement to induce thymocyte apoptosis. Therefore, we propose to analyze the role of galectin-1 in TCR mediated thymocyte positive and negative selection (Aim 1). Galectin-1 is also expressed by a subset of activated T cells. In some mature T cell populations, galectin-1 can cooperate with TCR engagement to enhance apoptosis, while antagonizing IL-2 production. Furthermore, galectin-1 can skew a Thl response to a Th2 response. Therefore, we propose to examine the role of galectin- 1 in mature T cell activation, differentiation and apoptosis (Aim 2). Finally, galectin- 1 expression is relatively high in resting CD4¿CD25 ¿regulatory T cells (Treg) and its expression is increased to even higher levels in activated Treg cells. Like the putative Treg cell effector, galectin-1 can function in trans to antagonize IL-2 production by antigen responsive T cells. Therefore, we propose to examine the role of galectin- 1 in Treg cell activity and the induction and the regulation of inflammatory bowel disease and tissue specific autoimmunity (Aim 3). While previous studies have primarily assessed the activity of T cell exposure to recombinant galectin-1, here we assess its endogenous activity. To address these issues we will analyze T cell development and responses of wild type and TCR transgenic T cells in which the galectin-1 gene has been ablated. In alternate approaches, we will characterize galectin-1 activity by differentiating or activating T cells in the presence of the newly developed galectin-1 inhibitor, L2hmda, or recombinant galectin-1. These studies will contribute to our basic understanding of T cell regulation, functional fate determination, and autoimmune disease prevention. Furthermore, they may identify novel targets for therapeutics aimed at inducing self tolerance for blocking autoimmunity and graft rejection or reversing tolerance to tumor antigens. PERFORMANCE SITE ========================================Section End===========================================

超出所提供的空间。 该提案代表了一系列研究，旨在评估内源性半乳糖凝集素-1 在调节 T 细胞发育、激活和耐受诱导中的潜在作用。拟议实验的基本原理源于我们的研究，将 galectin-1 定义为新型 T 细胞调节剂，能够调节 TCR 信号以选择性地调节功能结果。通过涉及 T 细胞突触内 T 细胞糖蛋白重组的独特分子机制，我们提出 galectin-1 可以对抗共刺激剂诱导的脂筏募集到突触以及持续的 TCR 信号转导。我们的初步研究结果预测，内源性半乳糖凝集素-1 可能在 T 细胞发育过程中设定 TCR 信号阈值以及防止 T 细胞过度活跃和自身免疫方面发挥作用。 Galectin-1 在整个胸腺中大量表达，可以与 TCR 配合诱导胸腺细胞凋亡。因此，我们建议分析galectin-1在TCR介导的胸腺细胞阳性和阴性选择中的作用（目标1）。 Galectin-1 也由活化的 T 细胞亚群表达。在一些成熟的 T 细胞群中，galectin-1 可以与 TCR 协同作用以增强细胞凋亡，同时拮抗 IL-2 的产生。此外，galectin-1可以使Th1反应偏向Th2反应。因此，我们建议研究 galectin-1 在成熟 T 细胞活化、分化和凋亡中的作用（目标 2）。最后，半乳糖凝集素-1 在静息 CD4 CD25 调节性 T 细胞 (Treg) 中表达相对较高，并且其表达在激活的 Treg 细胞中增加至更高水平。与假定的 Treg 细胞效应器一样，galectin-1 可以反式发挥作用，拮抗抗原反应性 T 细胞产生的 IL-2。因此，我们建议研究galectin-1在Treg细胞活性以及炎症性肠病和组织特异性自身免疫的诱导和调节中的作用（目标3）。虽然之前的研究主要评估了 T 细胞暴露于重组半乳糖凝集素-1 的活性，但在这里我们评估其内源活性。为了解决这些问题，我们将分析野生型和半乳糖凝集素-1 基因已被消除的 TCR 转基因 T 细胞的 T 细胞发育和反应。在替代方法中，我们将通过在新开发的 galectin-1 抑制剂 L2hmda 或重组 galectin-1 存在的情况下分化或激活 T 细胞来表征 galectin-1 活性。这些研究将有助于我们对 T 细胞调节、功能命运决定和自身免疫性疾病预防的基本了解。此外，他们可能会确定新的治疗靶标，旨在诱导自我耐受，以阻断自身免疫和移植物排斥或逆转对肿瘤抗原的耐受。表演网站==========================================章节结束===============================================