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.

项目摘要/摘要 当T淋巴细胞参与免疫反应时，它必须分裂并产生 功能性的子细胞通常反复反复。为了维持继续，克隆生产 新鲜效应t细胞要求某些子细胞自我更新而不是 区分。我们的实验室确定了诱导祖细胞T的激活信号 细胞以不可逆地承诺分化。保存自我更新， 但是，需要一种阻尼机制以完全激活。最重要的是 抑制T细胞激活的关键信号是抑制受体，现在是 释放T细胞攻击肿瘤的革命方法的主要目标。尽管 在某些情况下，抑制抑制受体的封锁可提供临床益处，许多治疗 患者没有耐用的抗肿瘤免疫力。这个项目解决了一部小说 以及临床上重要的问题，可能代表改善的主要障碍 抑制受体阻断的功效：抑制信号是A的重要组成部分 再生机制允许某些T细胞自我更新为它们的亲属细胞 经历差异化？使用癌症的临床前模型和慢性活动感染力 疾病，将解决3个特定目标：（1）确定抑制受体是否是否 封锁影响T细胞分化和体内自我更新的平衡，（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 抑制性的重复，高级抗原激活和反应强化 封锁和（3）测试抑制受体阻滞的功效是否会 通过添加促进T细胞自我更新的药物改善。这些结果 研究可以提供新颖的免疫反应生物标志物，新的疫苗接种策略， 以及新颖或重新利用的化合物，以增强免疫疗法的功效。