组蛋白H3K27去甲基化酶Jmjd3在胸腺髓质上皮细胞发育分化和建立T细胞中枢免疫耐受中的关键作用

Promiscuous expression and presentation of tissue-restricted self-antigens by medullary thymic epithelial cells (mTECs) lead to the deletion of self-reactive T cells and the generation of regulatory T cells during the establishment of T cell central tolerance. The mechanisms undying mTEC development/ differentiation and the establishment of central tolerance remain elucidated. We found the deficiency in mTEC development/ differentiation in Bcl-3/NFkB doubly deficient mice, suggesting Bcl-3-mediated epigenetic regulation in addition to alternative NFkB signaling might be involved in mTEC development/differentiation and the establishment of T cell central tolerance. Gene array analysis revealed that RANK activation unregulated H3K27 demethylase, JMJD3. Jmjd3 expression is dynamically consistent with mTEC development. Preliminary study from JMJD3 deficient mice indicated Jmjd3 play a crucial role in mTEC development. This project will employ Jmjd3 conditional mouse model to further verify the critical regulatory role of Jmjd3 in mTEC development and the presentation of self-antigens, to identify the gene network regulated by Jmjd3, and to explore the programmed events during mTEC development. This project will help elucidate the mechanisms underlying the establishment of T cell central tolerance, providing a theoretical basis for the development of potential immunointerference strategies for the diseases such as autoimmune diseases and tumor based on thymus regeneration and breakdown or re-establishment of central tolerance.

胸腺髓质上皮细胞（mTECs）表达递呈自身抗原，去除自身反应性T细胞和产生调节性T细胞，建立T细胞中枢免疫耐受。mTECs 的发育分化及自身抗原表达递呈的调控机制尚不完全明了。我们在Bcl-3/NFkB2双敲除小鼠中发现mTECs发育分化缺陷，提示除了非经典NFkB信号外，Bcl-3可能介导的表观遗传机制在其中起重要作用。通过基因芯片筛选，发现RANK信号能诱导H3K27去甲基化酶Jmjd3表达；其在胸腺发育过程中的动态表达与mTEC发育一致；在基因敲除小鼠中发现Jmjd3在mTEC发育分化中起关键作用。本项目将利用Jmjd3条件敲除小鼠进一步验证Jmjd3在mTECs发育分化和自身抗原表达中的调控作用，阐明其表观遗传调控机制，探究调控mTEC发育分化的基因网络和程序性事件。本项目将有助于阐明mTEC发育分化和建立T细胞中枢免疫耐受机制，为设计针对自身免疫病和肿瘤的干预策略奠定基础。

胸腺髓质上皮细胞（mTECs）表达递呈自身抗原，去除自身反应性T细胞和产生调节性T细胞，建立T细胞中枢免疫耐受，但mTECs的发育分化及自身抗原表达递呈的调控机制尚不完全明了。我们在Bcl-3/NFκB2双敲除小鼠中发现mTECs发育分化缺陷，提示除了非经典NFκB信号外，Bcl-3可能介导的表观遗传机制在其中起重要作用。同时，通过基因芯片筛选，我们还发现RANK信号能诱导H3K27去甲基化酶Jmjd3表达，其在胸腺发育过程中的动态表达与mTEC发育一致，且在基因敲除小鼠中发现Jmjd3在mTEC发育分化中起关键作用。. 基于上述发现，本项目主要利用Jmjd3基因条件性敲除小鼠研究了Jmjd3对胸腺髓质上皮细胞发育、分化和功能的影响，阐明了Jmjd3调控自身免疫症状的分子机制。具体发现包括：①Jmjd3敲除导致出生后小鼠胸腺髓质上皮细胞发育和功能障碍；②Jmjd3敲除影响了胸腺髓质上皮细胞存活和组织抗原基因表达；③Jmjd3调控抗凋亡基因Bcl-2和组织抗原基因的H3K27Me3修饰。. 这一研究进一步验证了Jmjd3在mTECs发育分化和自身抗原表达中的调控作用，阐明了其表观遗传调控机制，并对调控mTEC发育分化的基因网络和程序性事件进行了深入探索。项目首次从表观遗传角度研究免疫学的核心问题——mTEC的发育分化和T细胞中枢免疫耐受机制。同时，率先结合非经典NFκB信号通路的激活功能研究mTECs的发育分化，在免疫学理论研究和NFκB信号研究方面均具有重要意义。更重要的是，这一研究对深入理解建立T细胞中枢免疫耐受的机制提供了重要理论依据，由此可针对引入T细胞免疫耐受降低自身免疫性疾病和移植排斥等免疫性疾病、或打破免疫耐受有效增强抗肿瘤免疫和抗病毒免疫的免疫应答等开发出有效的免疫治疗新策略。