TGF-beta 1 Regulation of Peripheral T Cell Tolerance

TGF-β1 对外周 T 细胞耐受性的调节

• 批准号: 7878767
• 负责人: Ming Li
• 金额: $ 13.82万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7878767
• 关键词: Address; Antigens; Arthritis; Autoimmune Diseases; Binding; CD8B1 gene; Cell Differentiation process; Cell physiology; Cells; Chronic; Collagen Arthritis; Data; Dendritic Cells; Development; Disease; Endocrine; Engineering; Ensure; Family; Gene Expression; Gene Expression Profile; Gene Targeting; Genes; Genetic Programming; Genetic Transcription; Goals; Homeostasis; Immune; Immune response; Immune system; Inflammatory; Knock-in Mouse; Knockout Mice; Leukocytes; Mediating; Molecular; Mouse Strains; Mus; Mutant Strains Mice; Pathway interactions; Peripheral; Phenotype; Principal Investigator; Regulation; Reporter; Research; Role; Signal Transduction; Site; Source; T cell differentiation; T cell response; T-Lymphocyte; Transforming Growth Factor beta Receptors; Transforming Growth Factors; Transgenic Mice; Type I Epithelial Receptor Cell; autocrine; base; cell type; cytokine; human TGFB1 protein; immunopathology; in vivo; inhibitor/antagonist; mouse model; paracrine; programs; receptor

DESCRIPTION (provided by applicant): Transforming growth factor-beta1 (TGF-beta1) is a potent suppressive cytokine with an essential role in immune homeostasis. TGF-beta1 can be produced by and can act on virtually all lineages of leukocytes. My preliminary studies show that T cells are the central targets of TGF-beta1, as mice with a T cell-specific deletion of TGF-beta receptor develop severe immunopathology. My long-term goal is therefore to decipher the molecular and cellular T cell tolerance mechanisms elicited by TGF-beta1 and apply them to the study of collagen-induced arthritis. To gain a better understanding of the molecular mechanisms, I have performed large-scale gene expression profile studies and identified new target genes involved in TGF-beta1 regulation of effector T cell differentiation. I have also developed unique mouse models for the study of the cellular T cell tolerance mechanisms. To identify cells that express TGF-beta1,1 have engineered a GFP reporter mouse strain, and have found that dendritic cells (DCs) and T cells express high levels of TGF-beta1. To investigate the cell type-specific function of TGF-beta1, I have generated a strain of TGF-beta1 conditional knockout mice. T cell-specific deletion of TGF-beta1 results in a chronic inflammatory disease, emphasizing the importance of T cell-produced TGF-beta1 in T cell tolerance. Based on these data, I hypothesize that TGF-beta1 essentially regulates peripheral T cell tolerance by targeting the T cell differentiation program; T cell-produced TGF-beta1 synergizes with DC-produced TGF-beta1 to ensure T cell tolerance in vivo; and these tolerance pathways are important regulators of collagen-induced arthritis. To further address these hypotheses, I plan the following specific aims: Aim 1. To define the molecular mechanisms by which TGF-beta1 regulates effector T cell differentiation. Aim 2. To determine the cellular mechanisms by which TGF-beta1 regulates T cell responses. Aim 3. To study the function of TGF-beta1 produced by T cells and dendritic cells in the regulation of collagen-induced arthritis. TGF-beta1 is an important molecule for immune cell functions. My goal is to study the mechanism by which TGF-beta1 regulates T lymphocyte activity and the development of arthritis.

描述（由申请人提供）：转化生长因子-BETA1（TGF-BETA1）是一种有效的抑制性细胞因子，在免疫稳态中起着至关重要的作用。 TGF-BETA1可以由几乎所有白细胞谱系产生，并且可以作用。我的初步研究表明，T细胞是TGF-BETA1的核心靶标，因为具有TGF-β受体的T细胞特异性缺失的小鼠会发展出严重的免疫病理学。因此，我的长期目标是破译TGF-BETA1引起的分子和细胞T细胞耐受性机制，并将其应用于胶原蛋白诱导的关节炎的研究。为了更好地了解分子机制，我进行了大规模的基因表达谱研究，并确定了与TGF-BETA1效应T细胞分化调控有关的新靶基因。我还开发了独特的小鼠模型来研究细胞T细胞耐受性机制。为了鉴定表达TGF-BETA1,1的细胞已经设计了GFP报告基因菌株，并发现树突状细胞（DCS）和T细胞表达高水平的TGF-BETA1。为了研究TGF-BETA1的细胞类型特异性功能，我产生了TGF-BETA1条件敲除小鼠的菌株。 TGF-BETA1的T细胞特异性缺失导致慢性炎症性疾病，强调了T细胞产生的TGF-BETA1在T细胞耐受性中的重要性。基于这些数据，我假设TGF-BETA1基本上通过靶向T细胞分化程序来调节外围T细胞的耐受性。 T细胞生产的TGF-BETA1与DC生产的TGF-BETA1协同，以确保体内T细胞耐受性；这些耐受性途径是胶原蛋白引起的关节炎的重要调节剂。 为了进一步解决这些假设，我计划以下特定目的：目的1。定义TGF-BETA1调节效应T细胞分化的分子机制。 目标2。确定TGF-BETA1调节T细胞反应的细胞机制。 目的3。研究由T细胞和树突状细胞在胶原蛋白诱导的关节炎调节中产生的TGF-BETA1的功能。 TGF-BETA1是免疫细胞功能的重要分子。我的目标是研究TGF-BETA1调节淋巴细胞活性和关节炎发展的机制。

项目成果

Foxo: in command of T lymphocyte homeostasis and tolerance.

• DOI: 10.1016/j.it.2010.10.005
• 发表时间: 2011-01
• 期刊: Trends in immunology
• 影响因子: 16.8
• 作者: Ouyang W;Li MO
• 通讯作者: Li MO

Autocrine transforming growth factor-β1 promotes in vivo Th17 cell differentiation.

• DOI: 10.1016/j.immuni.2011.03.005
• 发表时间: 2011-03-25
• 期刊: Immunity
• 影响因子: 32.4
• 作者: Gutcher I;Donkor MK;Ma Q;Rudensky AY;Flavell RA;Li MO
• 通讯作者: Li MO

Transforming growth factor-beta signaling curbs thymic negative selection promoting regulatory T cell development.

• DOI: 10.1016/j.immuni.2010.04.012
• 发表时间: 2010-05-28
• 期刊: Immunity
• 影响因子: 32.4
• 作者: Ouyang W;Beckett O;Ma Q;Li MO
• 通讯作者: Li MO

T cell surveillance of oncogene-induced prostate cancer is impeded by T cell-derived TGF-β1 cytokine.

• DOI: 10.1016/j.immuni.2011.04.019
• 发表时间: 2011-07-22
• 期刊: Immunity
• 影响因子: 32.4
• 作者: Donkor MK;Sarkar A;Savage PA;Franklin RA;Johnson LK;Jungbluth AA;Allison JP;Li MO
• 通讯作者: Li MO