Foxp transcription factors in regulatory T cells

调节性 T 细胞中的 Foxp 转录因子

• 批准号: 10347180
• 负责人: JONATHAN S MALTZMAN
• 金额: --
• 依托单位: VETERANS ADMIN PALO ALTO HEALTH CARE SYS
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10347180
• 关键词: Address; Adoptive Transfer; Autoantibodies; Autoimmune; Autoimmune Diseases; Autoimmunity; CD4 Positive T Lymphocytes; Caring; Cells; Cellularity; DNA Binding; Data; Development; Disease model; Exhibits; Experimental Autoimmune Encephalomyelitis; FOXP1 gene; FOXP3 gene; Family; Family member; Gene Expression; Gene Expression Regulation; Generations; Genes; Genetic Transcription; Goals; Heart Transplantation; Hematopoietic System; Heterodimerization; High-Throughput Nucleotide Sequencing; Homeostasis; Homo; Human; Immune; Immune Tolerance; Immune response; Immunosuppression; Impairment; Infiltration; Inflammatory Bowel Diseases; Lead; Lymphocyte; Lymphocyte Activation; Lymphoid Tissue; Maintenance; Mediating; Modeling; Molecular; Mouse Strains; Mus; Mutation; Organ Transplantation; Peripheral; Phenotype; Population; Production; Regulation; Regulatory T-Lymphocyte; Role; Self Tolerance; Solid; System; T-Lymphocyte; T-Lymphocyte Subsets; Technology; Testing; Thymus Gland; Transplantation; Validation; Veterans; base; clinically relevant; dimer; improved; in vivo; in vivo Model; in vivo evaluation; member; novel; premature; transcription factor; translational approach; transplant model

Regulatory T cells (Tregs) are critical for actively maintaining immune tolerance. The Foxp family of transcription factors is composed of four members; Foxp1, Foxp3 and Foxp4 are expressed in lymphocytes. Foxp family members bind DNA as homo- and hetero-dimers to regulate gene expression. Regulatory T cells are CD4+ T cells that express Foxp3. We have generated mice in which both Foxp1 and Foxp4 are deleted in either all T lymphocytes or in Tregs, leaving Foxp3 the only potentially expressed family member in this T cell subset. Our preliminary data demonstrate that combined loss of Foxp1 and Foxp4 in all T lymphocytes based on CD4 Cre-mediated deletion substantially alters the development of Tregs in the thymus, reduces peripheral Treg cellularity, and alters suppressive function. When loss of Foxp1 and Foxp4 is limited to the Foxp3+ Treg population, there is a dramatic phenotype characterized by lymphocyte activation/expansion, autoantibody production, and early lethality. The overall goal of this proposal is to understand how Foxp1 and Foxp4 alter the development, homeostasis and function of Foxp3+ Tregs. To address this question we propose to generate and use novel mouse strains in which Foxp1 and Foxp4 are deleted at different stages of Treg development. We will use high throughput sequencing technology to investigate gene regulation by Foxp1 and/or Foxp4. We will test Tregs deficient in Foxp1 and Foxp4 in relevant models of autoimmunity and transplantation. Understanding these fundamental aspects of Treg generation, homeostasis and function are critical to translational strategies of Treg augmentation being developed for use in autoimmune disease and solid-organ transplantation.

调节性T细胞是主动维持免疫耐受的关键。FoxP家族的 转录因子由四个成员组成：Foxp1、Foxp3和Foxp4在淋巴细胞中表达。 FoxP家族成员以同源和异源二聚体的形式与DNA结合，调节基因表达。调节性T细胞 是表达Foxp3的CD4+T细胞。我们已经产生了Foxp1和Foxp4同时缺失的小鼠 所有的T淋巴细胞或在Tregs中，使Foxp3成为该T细胞中唯一可能表达的家族成员 子集。我们的初步数据显示，在所有T淋巴细胞中，Foxp1和Foxp4的联合缺失 在CD4Cre介导的缺失实质上改变胸腺中Tregs的发育，减少外周 Treg细胞密度，并改变抑制功能。当Foxp1和Foxp4的丢失仅限于Foxp3+Treg时 在人群中，有一种戏剧性的表型，其特征是淋巴细胞活化/扩增，自身抗体 生产和早期致命性。本提案的总体目标是了解Foxp1和Foxp4如何更改 Foxp3+Tregs的发育、动态平衡及其功能为了解决这个问题，我们建议 产生和使用在Treg的不同阶段缺失Foxp1和Foxp4的新小鼠品系 发展。我们将使用高通量测序技术来研究Foxp1对基因的调控 和/或Foxp4。我们将在相关的自身免疫模型中检测Foxp1和Foxp4缺陷的Tregs，并 移植。了解Treg生成、动态平衡和功能的这些基本方面 Treg增强的翻译策略被开发用于自身免疫性疾病和 实体器官移植。