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: 6675798
• 负责人: M CARRIE MICELI
• 金额: $ 19.06万
• 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/6675798
• 关键词: T cell receptor; T lymphocyte; apoptosis; autoimmunity; biological signal transduction; cell differentiation; genetically modified animals; immune tolerance /unresponsiveness; inflammatory bowel diseases; interleukin 2; laboratory mouse; lectin; leukocyte activation /transformation; lipid transport; membrane lipids; organ culture; protein biosynthesis; thymus

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（由申请人提供）：该提案代表一系列研究，旨在评估内源性半乳糖素-1在调节T细胞发育，激活和耐受性诱导中的潜在作用。提出的实验的基本原理源于我们将Galectin-1定义为新型T细胞调节剂的研究，能够调整TCR信号以选择性调节功能结果。通过涉及T细胞突触中T细胞糖蛋白重组的独特分子机制，我们建议Galectin-1反对伴奏刺激剂诱导的脂质筏募集到突触，并进行了过程和持续的TCR信号传输。我们的初步发现预测，内源性半乳糖素1可能在设置TCR信号传导阈值的过程中起作用，并预防T细胞多动和自身免疫性。 galectin-1在整个胸腺中大量表达，并且可以与TCR参与以诱导胸腺细胞凋亡。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（AIM 1）。 Galectin-1也通过激活的T细胞的子集表达。在某些成熟的T细胞群体中，Galectin-1可以与TCR参与度合作以增强凋亡，同时拮抗IL-2产生。此外，Galectin-1可能会对Th2响应的Th1响应偏斜。因此，我们建议检查半乳糖素1在成熟T细胞激活，分化和凋亡中的作用（AIM 2）。最后，在静止的CD4+ CD25+调节性T细胞（TREG）中，半表达相对较高，并且其表达在激活的Treg细胞中增加到更高的水平。像推定的Treg细胞效应子一样，Galectin-1可以通过抗原反应性T细胞拮抗IL-2的反式发挥作用。因此，我们建议检查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（AIM 3）。虽然先前的研究主要评估了T细胞暴露于重组lectectin-1的活性，但在这里我们评估了其内源性活性。为了解决这些问题，我们将分析T细胞的发育以及植物学1基因的野生型和TCR转基因T细胞的反应。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lectectin-1的情况下区分或激活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，功能性命运确定和自身免疫性疾病预防的基本理解。此外，他们可能会确定旨在诱导自耐力阻断自身免疫和移植排斥或逆转对肿瘤抗原的耐受性的新型治疗靶标。