Self-renewing Lymphocyte Division in The Immune Response

免疫反应中的自我更新淋巴细胞分裂

• 批准号: 10395010
• 负责人: STEVEN L REINER
• 金额: $ 40.19万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-02-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10395010
• 关键词: Acute; Address; Antigens; Automobile Driving; Biological; CD8-Positive T-Lymphocytes; Cancer Model; Cell division; Cells; Chronic; Clinical; Communicable Diseases; Confocal Microscopy; Daughter; Effector Cell; Equilibrium; Flow Cytometry; Functional disorder; Immune response; Immune system; Immunity; Immunotherapy; Infection; Interphase; Laboratories; Lymphocyte; Malignant Neoplasms; Mitotic; Monitor; Mus; Natural regeneration; PD-1 blockade; Patients; Physiological; Play; Pre-Clinical Model; Production; Role; Siblings; Signal Transduction; Sister; T cell differentiation; T cell response; T-Cell Activation; T-Lymphocyte; Testing; Therapeutic; Time; Tissues; Treatment Efficacy; Tumor Immunity; Virus; acute infection; anti-PD-1; anti-cancer; cell regeneration; chronic infection; daughter cell; design; disorder control; effector T cell; exhaustion; improved; in vivo; kindred; novel; preservation; progenitor; programmed cell death protein 1; receptor; regenerative; response; response biomarker; self renewing cell; self-renewal; stem cells; tumor; vaccination strategy

Project Summary/Abstract When a T lymphocyte is engaged in an immune response, it must divide and produce functional daughter cells, often repeatedly. To maintain continued, clonal production of fresh effector T cells requires that some daughter cells self-renew instead of differentiating. Our laboratory identified the activating signals that induce progenitor T cells to undergo irreversible commitment to differentiation. Preservation of self-renewal, however, requires a dampening mechanism to oppose full activation. Among the most critical signals that dampen T cell activation are the inhibitory receptors, which are now key targets of a revolutionary approach to unleash T cell attack against tumors. While blockade of inhibitory receptors offers clinical benefit in some cases, many treated patients do not experience durable anti-tumor immunity. This project addresses a novel and clinically important question that may represent a major barrier for improving the efficacy of inhibitory receptor blockade: Are inhibitory signals an essential part of a regenerative mechanism allowing some T cells to self-renew as their kindred cells undergo differentiation? Using preclinical models of cancer and chronic-active infectious diseases, 3 specific aims will be addressed: (1) Determine if inhibitory receptor blockade impacts the balance of T cell differentiation and self-renewal in vivo, (2) Define the cell biological mechanisms that support T cell self-renewal under in vivo conditions of repetitive, high-level antigen activation and response intensification by inhibitory blockade, and (3) Test whether the efficacy of inhibitory receptor blockade will be improved by addition of agents that promote T cell self-renewal. The results of these studies could offer novel immune response biomarkers, new strategies for vaccination, and novel or repurposed compounds to augment the efficacy of immunotherapy.

项目总结/摘要 当T淋巴细胞参与免疫反应时，它必须分裂并产生 有功能的子细胞，经常重复。为了维持持续的克隆生产， 新鲜的效应T细胞需要一些子细胞自我更新，而不是 差异化我们的实验室确定了诱导祖T细胞的激活信号， 细胞经历不可逆的分化承诺。保持自我更新， 但是需要阻尼机构来抵抗完全激活。的最 抑制T细胞活化的关键信号是抑制性受体，它们现在是 这是一种革命性方法的关键目标，可以释放T细胞攻击肿瘤。而 在某些情况下，抑制性受体的阻断提供了临床益处， 患者不会经历持久的抗肿瘤免疫。这个项目涉及一本小说 和临床上重要的问题，这可能是改善 抑制性受体阻滞剂的功效：抑制性信号是否是 再生机制允许一些T细胞自我更新为它们的亲属细胞 进行分化？使用癌症和慢性活动性感染的临床前模型， 疾病，3个具体目标将被解决：（1）确定是否抑制受体 阻断影响体内T细胞分化和自我更新的平衡，（2）定义 在体内条件下支持T细胞自我更新的细胞生物学机制 重复的，高水平的抗原激活和反应强化的抑制 阻断，和（3）测试抑制性受体阻断的功效是否将被抑制。 通过添加促进T细胞自我更新的试剂来改善。的结果予以 研究可以提供新的免疫反应生物标志物，新的疫苗接种策略， 和新的或再利用的化合物以增强免疫治疗的功效。