IKZF2通过Akt1/SIRT1信号途径调控银屑病中CD4+CD25highFOXP3+Treg细胞稳定性的研究

It has been identified that the overactivation of effector T cells due to the decreased function of CD4+CD25highFOXP3+Treg cells (Tri-Treg) plays important roles in psoriasis. Our previous study demonstrated that psoriatic Tri-Treg cells were not stable and they could transferred into effector T cells through mTORC2-Akt1 activation under streptococcus infections. Recent research found that IKZF2+ Tri-Treg cells showed strong stability with unknown mechanism. The deacetylase SIRT1 is involved in the regulation FOXP3 stability by its deacetylase activity through nucleus-cytoplasm translocation. Beased on previous results, we propose that IKZF2 regulates Tri-Treg stability by inflencing FOXP3 degradation through controling Akt1 activation and SIRT1 nucleus-cytoplasm translocation. In this project, we will observe and analyze IKZF2's effects on FOXP3 acetylation and stability in Tri-Treg cells on the levels of cells and animal modes. We will identify the detailed molecular mechanism by which IKZF2 regulates FOXP3 and Tri-Treg stability through analyzing Akt1 activation and SIRT1 nucleus-cytoplasm translocation. Our study will help to establish good foundation for the identification of immunological abnormality in autoimmne disorders like psoriasis.

CD4+CD25highFOXP3+Treg细胞（Tri-Treg）抑制功能下降，导致效应性T细胞过度活化是银屑病免疫学紊乱的重要环节。我们证明，银屑病中Tri-Treg细胞不稳定，在链球菌等感染下通过mTORC2-Akt1轴的活化可失去FOXP3，转变为效应性T细胞。同时发现，IKZF2+ Tri-Treg亚群稳定性强，但机制不清。去乙酰化酶SIRT1降低FOXP3乙酰化，通过核浆转运调控其稳定性。结合前期基础，我们提出IKZF2通过抑制Akt1亚型活化来调节SIRT1，影响FOXP3降解，调控Tri-Treg稳定性。本项目拟在细胞和动物模型等水平上观察分析IKZF2对Tri-Treg细胞中FOXP3乙酰化和稳定性的影响，并通过分析Akt1活化和SIRT1的核浆转运来明确IKZF2调控FOXP3和Tri-Treg稳定性的具体分子机制，为阐明银屑病等自身免疫性疾病的免疫紊乱机制奠定基础。

CD4+CD25highFOXP3+Treg细胞（Tri-Treg）抑制功能下降，导致效应性T细胞过度活化是银屑病免疫学紊乱的重要环节。我们证明，银屑病中Tri-Treg细胞不稳定，在链球菌等感染下通过mTORC2-Akt1轴的活化可失去FOXP3，转变为效应性T细胞。同时发现，IKZF2+ Tri-Treg亚群稳定性强，但机制不清。去乙酰化酶SIRT1降低FOXP3乙酰化，通过核浆转运调控其稳定性。结合前期基础，我们提出IKZF2通过抑制Akt1亚型活化来调节SIRT1，影响FOXP3降解，调控Tri-Treg稳定性。本项目拟在细胞和动物模型等水平上观察分析IKZF2对Tri-Treg细胞中FOXP3乙酰化和稳定性的影响，并通过分析Akt1活化和SIRT1的核浆转运来明确IKZF2调控FOXP3和Tri-Treg稳定性的具体分子机制，为阐明银屑病等自身免疫性疾病的免疫紊乱机制奠定基础。