ROLE OF ICOS IN T CELL RESPONSES AND ANTI-TUMOR IMMUNITY

ICOS 在 T 细胞反应和抗肿瘤免疫中的作用

• 批准号: 6329108
• 负责人: Gordon James Freeman
• 金额: $ 22.38万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-12-13 至 2004-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6329108
• 关键词: CD28 molecule; T cell receptor; T lymphocyte; antigen presenting cell; antineoplastics; biological signal transduction; cell differentiation; cell proliferation; chimeric proteins; disease /disorder model; gene expression; gene interaction; helper T lymphocyte; immunoregulation; immunosuppression; interleukin 10; interleukin 4; laboratory mouse; laboratory rat; leukocyte activation /transformation; monoclonal antibody; neoplasm /cancer genetics; neoplasm /cancer immunology; phosphatidylinositol 3 kinase; receptor expression

The BY-CD28/CTLA-4 co-stimulatory pathway has a critical role in regulating T cell activation, and manipulation of this key immunoregulatory pathway has great therapeutic potential. We have cloned a novel murine gene that is a third member of the CD28/CTLA4 gene family and is the murine homologue of the recently described human ICOS (Inducible Co-stimulatory) gene. ICOS is expressed on activated murine T cells and expression as restricted to T cells, similarly to CD28 and CTLA4. In humans, ICOS functions as a receptor for co-stimulatory signals leading to T cell proliferation and production of IL-4 and IL-10, but not IL-2. The relationships of ICOS with the receptors and ligands in the B7-CD28/CTLA-4 pathway need to be define. It is not yet known whether ICOS binds B7 co-stimulators or if ICOS binds to an as yet to be identified counter-receptor in a parallel pathway. It is also not clear when ICOS co-stimulation is needed during immune response. Because ICOS stimulates IL-4 and super-induces IL-10 production, ICOS co-stimulation may have an important role in T cell differentiation and the generation of regulatory T cells. Therefore, manipulation of ICOS signaling may have therapeutic potential. The goal of this research project is to elucidate the role of ICOS co-stimulation in T cell activation, differentiation, and tumor immunity. We have developed a murine ICOS fusion protein that enables us to analyze the function of ICOS on naive and previously activated T cells to characterize the expression and function of ICOS counter-receptor, and to analyze the function of ICOS interactions with the B7/CD28 pathway. In this project, we will characterize how ICOS functions as a receptor for co-stimulator signals from antigen presenting cells and how ICOS regulates T cell proliferation and differentiation. We will examine the role of ICOS co-stimulation in the generation of an effective anti-tumor response in vivo using the EL4 tumor model since the role of IL-4 and IL-10 in suppression of effective tumor immunity has been well defined in this model. ICOS function may deviate the immune response away from a protective cytolytic anti-tumor response and towards a suppressive anti-tumor Th2 response. To understand the role of ICOS in the T cell response and in anti-tumor immunity, I propose to: SPECIFIC AIM 1. To examine the role of ICOS in T cell activation and differentiations. SPECIFIC AIM 2. To examine the expression the expression of ICOS counter-receptor on APC and characterize its molecular structure. SPECIFIC AIM 3. To examine how blocking ICOS signals affect the immune response to murine tumors.

BY-CD 28/CTLA-4共刺激通路在调节T细胞活化中具有关键作用，并且操纵该关键免疫调节通路具有巨大的治疗潜力。我们已经克隆了一个新的小鼠基因，它是CD 28/CTLA 4基因家族的第三个成员，并且是最近描述的人ICOS（诱导共刺激）基因的小鼠同源物。ICOS在活化的鼠T细胞上表达，并且表达限于T细胞，类似于CD 28和CTLA 4。在人类中，ICOS作为共刺激信号的受体发挥作用，导致T细胞增殖和产生IL-4和IL-10，但不产生IL-2。ICOS与B7-CD 28/CTLA-4通路中受体和配体的关系尚需明确。目前尚不清楚ICOS是否结合B7共刺激分子，或者ICOS是否在平行途径中结合到尚未鉴定的反受体。也不清楚在免疫应答期间何时需要ICOS共刺激。由于ICOS刺激IL-4并超诱导IL-10产生，因此ICOS共刺激可能在T细胞分化和调节性T细胞的产生中具有重要作用。因此，操纵ICOS信号传导可能具有治疗潜力。本研究项目的目标是阐明ICOS共刺激在T细胞活化、分化和肿瘤免疫中的作用。我们已经开发了一种鼠ICOS融合蛋白，使我们能够分析ICOS对初始和先前活化的T细胞的功能，以表征ICOS反受体的表达和功能，并分析ICOS与B7/CD 28通路相互作用的功能。在这个项目中，我们将描述ICOS如何作为抗原呈递细胞共刺激信号的受体以及ICOS如何调节T细胞增殖和分化。我们将使用EL 4肿瘤模型检查ICOS共刺激在体内产生有效抗肿瘤应答中的作用，因为IL-4和IL-10在抑制有效肿瘤免疫中的作用已经在该模型中得到很好的定义。ICOS功能可能使免疫应答偏离保护性溶细胞抗肿瘤应答，而偏向抑制性抗肿瘤Th 2应答。为了了解ICOS在T细胞应答和抗肿瘤免疫中的作用，我建议：特异性目的1。研究ICOS在T细胞活化和分化中的作用。具体目标2.检测ICOS反受体在APC上的表达，并对其分子结构进行表征。具体目标3.研究阻断ICOS信号如何影响对小鼠肿瘤的免疫应答。