Foxp transcription factors in regulatory T cells

调节性T细胞（TCRs）对于积极维持免疫耐受至关重要。Foxp家族 转录因子由四个成员组成; Foxp 1、Foxp 3和Foxp 4在淋巴细胞中表达。 Foxp家族成员结合DNA作为同源和异源二聚体来调节基因表达。调节性T细胞 是表达Foxp 3的CD 4 + T细胞。我们已经产生了Foxp 1和Foxp 4都缺失的小鼠， 所有的T淋巴细胞或在T淋巴细胞中，使得Foxp 3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表明，所有T淋巴细胞中Foxp 1和Foxp 4的联合缺失， 在CD 4 Cre介导的缺失上， Treg细胞结构，并改变抑制功能。当Foxp 1和Foxp 4的缺失仅限于Foxp 3 + Treg时， 人群中，存在以淋巴细胞活化/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Foxp 1和Foxp 4如何改变 Foxp 3 + T细胞的发育、稳态和功能。为了解决这个问题，我们建议 产生和使用新的小鼠品系，其中Foxp 1和Foxp 4在Treg的不同阶段缺失 发展我们将使用高通量测序技术来研究Foxp 1的基因调控 和/或Foxp 4。我们将在相关的自身免疫模型中检测Foxp 1和Foxp 4缺陷的TcR， 移植了解Treg生成、稳态和功能的这些基本方面是 对于开发用于自身免疫性疾病的Treg增强的翻译策略至关重要， 实体器官移植

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.