Foxp transcription factors in regulatory T cell development and homeostasis

Foxp 转录因子在调节性 T 细胞发育和稳态中的作用

• 批准号: 8915931
• 负责人: JONATHAN S MALTZMAN
• 金额: $ 39.61万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8915931
• 关键词: Address; Autoimmune Diseases; Autoimmunity; CD4 Positive T Lymphocytes; Cell surface; Cells; Cellularity; Chronic; Complex; Cytokine Receptors; Cytokine Signaling; DNA Binding; Data; Development; Disadvantaged; Employee Strikes; Exhibits; Family; Family member; Gene Expression; Generations; Genetic Transcription; Goals; Health; Hematopoietic System; Homeostasis; Homo; Human; Immune Tolerance; Immune response; Immunosuppression; Immunosuppressive Agents; In Vitro; Inflammatory Bowel Diseases; Lead; Left; Life; Lymphocyte; Maintenance; Mediating; Modeling; Morbidity - disease rate; Mouse Strains; Mus; Mutation; Organ Transplantation; Pathway interactions; Peripheral; Phenotype; Phosphorylation; Population; Publishing; Receptor Signaling; Regulatory T-Lymphocyte; Relative (related person); Role; STAT5A gene; Signal Pathway; Signal Transduction; Solid; Staging; System; T-Cell Development; T-Cell Receptor; T-Lymphocyte; T-Lymphocyte Subsets; Thymus Gland; Transplantation; cytokine; dimer; in vivo; member; novel; receptor expression; response; thymocyte; transcription factor

DESCRIPTION (provided by applicant): 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 T lymphocytes, 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 T lymphocytes substantially alters the development of Tregs in the thymus, reduces peripheral Treg cellularity, and alters suppressive function. Treg development relys on a complex interaction of signals generated by the T cell receptor, costimulatory pathways and cytokine receptors. 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 novel mouse strains in which Foxp1 and Foxp4 are deleted at different stages of Treg development. We will manipulate signaling pathways to determine if the alterations in Foxp1/Foxp4 deficient Tregs are due to altered TCR or cytokine signaling. We will determine if loss of Foxp1 and Foxp4 in Tregs alters in vivo responses in models of transplantation and inflammatory bowel disease. 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.

描述（由申请人提供）：调节性 T 细胞 (Treg) 对于主动维持免疫耐受至关重要。 Foxp转录因子家族由四个成员组成~Foxp1、Foxp3和Foxp4在淋巴细胞中表达。 Foxp 家族成员以同源二聚体和异源二聚体形式结合 DNA 来调节基因表达。 调节性 T 细胞是表达 Foxp3 的 CD4+ T 细胞。我们培育了 T 淋巴细胞中 Foxp1 和 Foxp4 均被删除的小鼠，使 Foxp3 成为该 T 细胞亚群中唯一可能表达的家族成员。 我们的初步数据表明，T 淋巴细胞中 Foxp1 和 Foxp4 的联合缺失显着改变了胸腺中 Treg 的发育，减少了外周 Treg 细胞结构，并改变了抑制功能。 Treg 发育依赖于 T 细胞受体、共刺激途径和细胞因子受体产生的信号的复杂相互作用。 该提案的总体目标是了解 Foxp1 和 Foxp4 如何改变 Foxp3+ Tregs 的发育、稳态和功能。 为了解决这个问题，我们建议产生新的小鼠品系，其中 Foxp1 和 Foxp4 在 Treg 发育的不同阶段被删除。 我们将操纵信号通路来确定 Foxp1/Foxp4 缺陷型 Tregs 的改变是否是由于 TCR 或细胞因子信号传导的改变所致。 我们将确定 Tregs 中 Foxp1 和 Foxp4 的缺失是否会改变移植和炎症性肠病模型的体内反应。了解 Treg 生成、稳态和功能的这些基本方面对于开发用于自身免疫性疾病和实体器官移植的 Treg 增强转化策略至关重要。