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: 7148099
• 负责人: M CARRIE MICELI
• 金额: $ 36.15万
• 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 2008-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7148099
• 关键词: Accounting; Address; Adoptive Transfer; Age; Antigens; Apoptosis; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Binding; CD4 Positive T Lymphocytes; Cell physiology; Cells; Chromosome Pairing; Condition; Data; Development; Effector Cell; Exposure to; Fetal Thymic Organ Culture; Galactose Binding Lectin; Galectin 1; Genes; Glycoproteins; Graft Rejection; In Vitro; Inflammatory; Inflammatory Bowel Diseases; Interleukin-2; Lymphokines; Mature T-Lymphocyte; Mediating; Mediator of activation protein; Membrane Microdomains; Modeling; Molecular; Monitor; Mus; Pathology; Pattern; Peripheral; Phenotype; Population; Principal Investigator; Production; Recombinants; Regulation; Relative (related person); Reporting; Research Design; Rest; Role; Self Tolerance; Series; Signal Transduction; Suppressor-Effector T-Lymphocytes; Synapses; T cell regulation; T-Cell Activation; T-Cell Development; T-Cell Proliferation; T-Lymphocyte; Testing; Thymocyte Development; Thymus Gland; Tissues; Transgenic Model; Transgenic Organisms; Tumor Antigens; base; disorder prevention; functional outcomes; in vivo; inhibitor/antagonist; insight; novel; prevent; programs; research study; response; reverse tolerance; stem; therapeutic target; thymocyte

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.

该提案代表了一系列旨在评估内源性半乳糖凝集素-1在以下方面的潜在作用的研究： 调节T细胞发育、活化和耐受诱导。拟议实验的基本原理 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， 调节功能结果。通过一种独特的分子机制，涉及T细胞的重组， 由于半乳糖凝集素-1与T细胞突触内的糖蛋白的相互作用，我们认为半乳糖凝集素-1对抗共刺激物诱导的脂筏 募集到突触以及进行性和持续的TCR信号转导。我们的初步发现预测 内源性半乳糖凝集素-1可能在T细胞发育过程中设定TCR信号传导阈值， 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，并且可以与TCR接合协作以诱导免疫应答。 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表达中的作用， 负选择（Aim 1）半乳糖凝集素-1也由活化的T细胞亚群表达。在一些成熟的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 生产此外，半乳糖凝集素-1可以使Thl应答偏向于Th 2应答。因此，我们建议 检测半乳糖凝集素-1在成熟T细胞活化、分化和凋亡中的作用（目的2）。最后，半乳凝素- 1在静息CD 4调节性T细胞（Treg）中表达相对较高，其表达增加至 在活化的Treg细胞中甚至更高的水平。与推定的Treg细胞效应子一样，半乳糖凝集素-1可以反式地发挥作用， 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的作用， 在Treg细胞活性和炎症性肠病的诱导和调节以及组织特异性 自身免疫（目的3）。虽然以前的研究主要评估了T细胞暴露于 重组半乳糖凝集素-1，在这里，我们评估其内源性活性。为了解决这些问题，我们将分析T细胞 其中半乳糖凝集素-1基因已被消除的野生型和TCR转基因T细胞的发育和应答。 在替代方法中，我们将通过分化或激活T细胞来表征半乳糖凝集素-1活性。 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的存在。这些研究将 有助于我们对T细胞调节、功能性命运决定和自身免疫性疾病的基本理解 预防此外，他们可能会确定新的治疗目标，旨在诱导自身耐受性， 阻断自身免疫和移植排斥或逆转对肿瘤抗原的耐受。