Foxp1对调节性T细胞和自身免疫病的调控作用

Foxp3+ regulatory T cells (Treg) exert an essential role in regulating immune tolerance and preventing the development of autoimmune diseases. The mechanisms controlling Treg remain unclear. Recent studies showed that the transcription factor Foxp1 is closely related to human autoimmune diseases, yet the role of Foxp1 in Treg is unknown. Our study reveal that Tregs lacking the transcription factor Foxp1 expression have defect in survival and express reduced levels of both the interleukin-2 recptor β subunit (IL-2Rβ) and Foxp3. We hypothesize that Foxp1 prevents the development of autoimmune diseases through up-regulating the expression of IL-2Rβ and Foxp3 in Tregs and promotes their survival and function. We planned to establish the Treg-specific Foxp1 knockout mice and T cell transfer colitis model, and utilize techniques including EMSA、chormatin immunoprecipitation and reporter assay, from a complete body-cell-molecule aspects to prove our hypothesis. The results of this project will for the first time reveal a novel Foxp1-mediated mechanism of maintaining immune tolerance and may provide new strategies for the treatment of immune diseases in the clinic.

Foxp3+ 调节性T细胞（Treg）对机体免疫耐受发挥重要的调节作用而防止自身免疫病的发生。控制Treg的分子机制未被阐明。最近的研究表明转录因子Foxp1与人类自身免疫性疾病密切关联，然而Foxp1对Treg的作用未知。我们的研究发现，缺少Foxp1的Treg 具有存活缺陷，并且其白介素-2受体β亚单位（IL-2Rβ）和Foxp3的表达水平同时下降。我们推测"Foxp1通过上调IL-2Rβ和Foxp3的表达而促进Treg存活和功能"是机体防止自身免疫病发生的重要机制。我们将建立Treg特异性Foxp1敲除小鼠和T细胞转移肠炎模型，应用凝胶迁移分析、染色质沉淀、报告基因等技术，从整体-细胞-分子三个层次验证我们的假说。本研究将首次揭示一种Foxp1介导的维持免疫耐受的新机制，可能为将来治疗免疫耐受相关性疾病提供新的思路和理论依据。

Foxp3+调节性T细胞（Treg）对机体免疫耐受发挥重要的调节作用而防止自身免疫病的发生。其谱系稳定性的核心内容是持续Foxp3的表达和免疫抑制功能的维持。我们通过筛选Foxp1相关的静息分子，筛选出AX基因对Treg控制很重要。在Treg中特异性敲除AX后，Treg的稳定性和抑制功能严重受损，从而导致免疫活化和自身免疫性疾病的发生。Treg的移植治疗在自身免疫病和造血干细胞（HSC）移植中有广泛的应用前景，因此，以AX为关键检查点干预Treg，来维持或恢复Treg谱系稳定性，从而抵抗炎症对Treg的损害作用，维持Treg数量和功能。对临床HSC疾病的治疗具有重要意义。同时研究还阐明静息分子Tsc1对树突状细胞功能的调控作用。