胸腺衰老和退化的表观遗传调控机制

The progressive thymic aging and involution with age lead to reduced naive T cell production and altered selection responsible for the increased susceptibility of a number of diseases such as tumor and infection. Thymic development and involution are based on the self-renew, differentiation survival and quiescence of thymic epithelial progenitor cells (TEPCs). However, mechanisms underlying age-associated thymic involution remain elusive. We have demonstrated that miR-449/34 regulate the self-renew, development/differentiation and survival of TEPCs, while H3K27Me3 modification mediated Jmjd3 modulates the development/differentiation and survival of medullary thymic epithelial cells (mTECs). These findings reveal that miR-34/449 and H3K27Me3 modification may be critical for thymic aging and involution. This project will employ miR-34/449 knockout mice and conditional knockout mice deleting Jmjd3 in TECs to decipher the mechanisms underlying regulation of miR-34/449 and H3K27Me3 modification on the self-renew, development/differentiation, survival and quiescence initiation of TEPCs and TECs. We will screen and find the key molecules that play important roles in thymic aging and involution, develop new approaches to delay or suppress the processes of thymic aging and involution, and provide novel strategies to prevent and treat the diseases such as cancers and infection.

伴随年龄增长，胸腺衰老和退化引起T细胞产生减少、选择异常，从而导致肿瘤和感染等多种疾病的易感性增加。胸腺的发育与衰老主要由胸腺上皮前体细胞（TEPC）的自我更新、分化、存活以及静息启动决定的。但调控胸腺衰老和退化的分子机制却仍不清楚。我们前期研究发现miR-34/449能调控TEPC自我更新和发育分化；H3K27去甲基化酶Jmjd3介导的H3K27甲基化修饰能调控胸腺髓质上皮细胞（mTEC）的存活，显示miR-34/449和H3K27甲基化修饰能调控胸腺的衰老和退化。本项目拟利用miR-34/449敲除小鼠和胸腺上皮细胞特异性敲除Jmjd3的小鼠两种独特小鼠模型深入研究miR-34/449和H3K27甲基化修饰调控TEPC和TEC自我更新、增殖分化、存活和静息启动的机制，发现调控胸腺衰老和退化的新分子，开发能延缓或抑制胸腺衰老和退化的新方法，为肿瘤和感染等疾病防治提供新策略。

胸腺上皮前体细胞发育分化为皮质区和髓质区胸腺上皮细胞（cortical and medullary thymic epithelial cells，cTECs和mTECs），决定胸腺的发育和衰老退化，特别是髓质区胸腺上皮细胞通过表达和递呈组织限制性抗原（tissue-restricted antigens，TRAs）在建立T细胞中枢免疫耐受中发挥核心作用。髓质胸腺上皮细胞发育分化、稳态维持和组织限制性抗原表达在胸腺衰老退化过程中起关键作用，但对其调控机制，尤其是表观遗传调控机制仍不清楚。本项目研究发现组蛋白H3第27位赖氨酸去甲基化酶Kdm6b介导的组蛋白修饰不调控胚胎期和出生后胸腺发育，但抑制胸腺衰老。不影响cTEC的发育分化，促进髓质胸腺上皮细胞的存活和调控组织限制性抗原基因的表达，但不影响mTEC的增殖，在维持小鼠出生后的胸腺髓质稳态中发挥关键作用。缺失Kdm6b的小鼠出现病理性的自身免疫异常，胸腺衰老加速。进一步研究发现，Kdm6b通过减少抗细胞凋亡基因Bcl2和一系列Aire依赖的组织限制性抗原基因启动子区的抑制性组蛋白H3第27位赖氨酸三甲基化发挥功能。因此，本项目研究揭示了组蛋白H3第27位赖氨酸去甲基化修饰通过调控mTEC的稳态维持和功能，促进T细胞中枢免疫耐受的建立，抑制胸腺衰老和退化，为以增强机体免疫力为目的的胸腺再生研究提供了重要的理论依据。