Foxp transcription factors in regulatory T cell development and homeostasis

描述(由申请人提供)：调节性T细胞(Treg)对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。我们已经产生了在T淋巴细胞中同时缺失Foxp1和Foxp4的小鼠，使得Foxp3成为这个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的联合丢失显著改变了胸腺中Treg的发育，减少了外周Treg细胞密度，并改变了抑制功能。Treg的发育依赖于T细胞受体、共刺激通路和细胞因子受体产生的信号的复杂相互作用。这个方案的总体目标是了解Foxp1和Foxp4是如何改变Foxp3+Treg的发育、动态平衡和功能的。为了解决这个问题，我们建议创造新的小鼠品系，其中Foxp1和Foxp4在Treg发育的不同阶段被缺失。我们将操纵信号通路来确定Foxp1/Foxp4缺陷Tregs的变化是由于TCR还是细胞因子信号的改变。我们将确定在移植和炎症性肠病模型中，Tregs中Foxp1和Foxp4的缺失是否会改变体内的反应。了解Treg生成、稳态和功能的这些基本方面，对于为自身免疫性疾病和实体器官移植开发Treg增强的翻译策略至关重要。

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.