Self-renewing Lymphocyte Division in The Immune Response

免疫反应中的自我更新淋巴细胞分裂

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/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细胞 T 的激活信号细胞经历不可逆的分化承诺。保持自我更新，然而，需要一个阻尼机制来阻止完全激活。其中最抑制 T 细胞激活的关键信号是抑制性受体，现在是释放 T 细胞攻击肿瘤的革命性方法的关键目标。尽管抑制性受体的阻断在某些情况下提供临床益处，许多接受治疗患者没有获得持久的抗肿瘤免疫力。该项目涉及一部小说以及临床上重要的问题，可能是改善病情的主要障碍抑制性受体阻断的功效：抑制信号是抑制信号的重要组成部分吗？再生机制允许一些 T 细胞像它们的同类细胞一样自我更新进行分化？使用癌症和慢性活动性传染病的临床前模型疾病，将解决 3 个具体目标：（1）确定抑制性受体阻断影响体内 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通过抑制重复、高水平的抗原激活和反应强化阻断，以及（3）测试抑制性受体阻断的功效是否会通过添加促进 T 细胞自我更新的药物来改善。这些结果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、以及新的或重新利用的化合物以增强免疫疗法的功效。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

IRF4 Couples Anabolic Metabolism to Th1 Cell Fate Determination.

IRF4 将合成代谢与 Th1 细胞命运决定结合起来。

DOI：
发表时间：
2017-09-01
期刊：
影响因子：
0
作者：
Kratchmarov, Radomir;Nish, Simone A;Lin, Wen;Adams, William C;Chen, Yen;Yen, Bonnie;Rothman, Nyanza J;Klein, Ulf;Reiner, Steven L
通讯作者：
Reiner, Steven L

Cutting edge: Lymphoproliferation caused by Fas deficiency is dependent on the transcription factor eomesodermin.

最前沿：Fas 缺乏引起的淋巴增殖依赖于转录因子脱中胚层蛋白。

DOI：
发表时间：
2010-12-15
期刊：
影响因子：
0
作者：
Kinjyo, Ichiko;Gordon, Scott M;Intlekofer, Andrew M;Dowdell, Kennichi;Mooney, Erin C;Caricchio, Roberto;Grupp, Stephan A;Teachey, David T;Rao, V Koneti;Lindsten, Tullia;Reiner, Steven L
通讯作者：
Reiner, Steven L

TCF1 expression marks self-renewing human CD8+ T cells.

TCF1 表达标志着自我更新的人类 CD8 T 细胞。