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: 6983416
• 负责人: M CARRIE MICELI
• 金额: $ 37.23万
• 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/6983416
• 关键词: Galectin; regulation; cell; activation; tolerance

DESCRIPTION (provided by applicant): 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 hyperactivity 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 Th1 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.

描述（由申请方提供）：本提案代表了一系列旨在评估内源性半乳糖凝集素-1在调节T细胞发育、活化和耐受诱导中的潜在作用的研究。所提出的实验的基本原理源于我们的研究将半乳糖凝集素-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。通过一个独特的分子机制，涉及重组的T细胞突触内的T细胞糖蛋白，我们建议，半乳糖凝集素-1反对共刺激诱导的脂筏招聘的突触和进行性和持续的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细胞发育过程中设置TCR信号转导阈值，并防止T细胞过度活跃和自身免疫。半乳糖凝集素-1在整个胸腺中大量表达，并可与TCR接合协同诱导胸腺细胞凋亡。因此，我们建议分析半乳糖凝集素-1在TCR介导的胸腺细胞阳性和阴性选择中的作用（目的1）。半乳糖凝集素-1也由活化的T细胞亚群表达。在一些成熟T细胞群中，半乳糖凝集素-1可以与TCR接合合作以增强凋亡，同时拮抗IL-2的产生。此外，半乳糖凝集素-1可以使Th 1应答偏向于Th 2应答。因此，我们建议研究半乳糖凝集素-1在成熟T细胞活化、分化和凋亡中的作用（目的2）。最后，半乳糖凝集素-1在静息的CD 4 + CD 25+调节性T细胞（Treg）中表达相对较高，并且其表达在活化的Treg细胞中增加至甚至更高的水平。与推定的Treg细胞效应子一样，半乳糖凝集素-1可以反式发挥作用以拮抗抗原应答性T细胞产生IL-2。因此，我们建议检查半乳糖凝集素-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（目的3）。虽然先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，但在此我们评估了其内源性活性。为了解决这些问题，我们将分析野生型和TCR转基因T细胞的T细胞发育和反应，其中半乳糖凝集素-1基因已被消融。在替代方法中，我们将通过在新开发的半乳糖凝集素-1抑制剂L2 hmda或重组半乳糖凝集素-1存在下分化或活化T细胞来表征半乳糖凝集素-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理解。此外，他们可能会确定新的治疗目标，旨在诱导自身耐受阻断自身免疫和移植排斥或逆转肿瘤抗原的耐受性。