Galectin-1 regulation of T cell activation and tolerance

超出提供的空间。这项建议代表了一系列旨在评估内源性Galectin-1在调节T细胞发育、激活和耐受诱导中的潜在作用的研究。建议实验的基本原理源于我们的研究定义Galectin-1是一种新型的T细胞调节因子，能够调节TCR信号来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，我们认为Galectin-1反对共刺激分子诱导的脂筏募集到突触和进行持续的TCR信号转导。我们的初步发现预测，内源性Galectin-1可能在T细胞发育过程中设定TCR信号阈值，并在防止T细胞过度活动和自身免疫方面发挥作用。Galectin-1在胸腺中大量表达，与TCR结合可诱导胸腺细胞凋亡。因此，我们建议分析Galectin-1在TCR介导的胸腺细胞正负选择中的作用(目标1)。Galectin-1也由活化的T细胞亚群表达。在一些成熟的T细胞群体中，Galectin-1可以协同TCR参与促进细胞凋亡，同时拮抗IL-2的产生。此外，Galectin-1可以使Th1反应向Th2反应倾斜。因此，我们建议研究Galectin-1在成熟T细胞激活、分化和凋亡中的作用(目标2)。最后，Galectin-1在静止的CD4？CD25？调节性T细胞(Treg)中的表达相对较高，而在激活的Treg细胞中其表达水平更高。与假定的Treg细胞效应器一样，Galectin-1可以通过反式作用对抗抗原反应性T细胞产生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)。虽然以前的研究主要评估T细胞对重组Galectin-1的暴露活性，但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Galectin-1基因已被去除的野生型和TCR转基因T细胞的T细胞发育和反应。在其他方法中，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的活性。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，它们可能为旨在诱导自身耐受以阻断自身免疫和移植物排斥反应或逆转对肿瘤抗原的耐受的治疗寻找新的靶点。表演网站========================================Section End===========================================

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===========================================