MANIPULATION OF LYMPHOCYTE HOMEOSTASIS ENHANCING ANTI-TUMOR IMMUNITY

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 我的项目的具体目标已经从这个项目开始时发生了变化，因为我们的实验室产生了新的和令人兴奋的发现，指出了肿瘤特异性细胞毒性T淋巴细胞(CTL)中的一种新的共刺激途径。我们已发表的初步数据表明，T淋巴细胞表达功能性的Toll样受体。例如，当过继转移到同一受者体内，然后注射TLR1/2配体和抗原时，CTL显示出比TLR2/OT-1 CTL更优先的扩增。 这项授权背后的假设是，体内CTL上TLR2的参与增强了克隆扩张，促进了记忆发展，并增强了它们的功能能力。主要目的是1)从机制上了解TLR2结合CTL如何促进克隆扩张和记忆发育，以及2)确定TLR2结合CTL增加效应分子表达从而增强抗肿瘤活性的分子机制。这些研究将有助于确定新的共刺激途径，从而为提高肿瘤特异性效应和记忆细胞的生成效率提供机会，并通过操纵CTL中的TLR信号来增强细胞溶解活性。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The specific aims to my project have changed from the inception of this program due to new and exciting findings generated in our laboratory that point to the identification of a novel co-stimulatory pathway in tumor specific cytotoxic T-lymphocytes (CTL). Our published and preliminary data indicate that T-lymphocytes express functional Toll-like receptors. For instance, CTLs show a preferential expansion over TLR2/OT-1 CTLs when adoptively transferred into the same recipient followed by injection with TLR1/2 ligand and antigen. The hypothesis underlying this grant is that the engagement of TLR2 on CTLs in vivo augments clonal expansion, facilitates memory development, and potentiates their functional capacity. The main objectives are to 1) achieve a mechanistic understanding of how TLR2 engagement on CTLs enhances clonal expansion and memory development and 2) determine the molecular mechanisms through which TLR2 engagement on CTLs augments the expression of effector molecules resulting in enhanced anti-tumor activity. These studies will help identify novel co-stimulatory pathways, thereby providing opportunities for increasing the efficiency with which tumor-specific effector and memory cells are generated and boosting cytolytic activity by manipulating TLR signaling in CTLs.