The role of medullary thymic epithelial cell-derived growth factors in regulating thymus growth and atrophy

摘要 T淋巴细胞是获得性免疫反应的关键介质，然而，它们不断丢失。 在整个寿命内，因此必须不断更换。胸腺是新T细胞的主要部位 细胞生成，独特的胸腺基质微环境指导T细胞分化，自我耐受和 自我约束。然而，胸腺的大小在生命的相对早期就开始急剧下降，结果 导致新的幼稚T细胞的产量下降。因此，动态平衡机制推动了记忆的扩展 外周血中的细胞，促使T细胞向寡克隆T细胞记忆转变，使老年人对 疫苗和新的感染，特别是病毒感染。预防或逆转年龄相关性胸腺萎缩 因此，在延长老龄化人口健康寿命方面具有巨大的潜力。治理机制 胸腺萎缩一直难以识别，因为萎缩的主要靶点是胸腺皮质间质 细胞，是稀有的，很难分离。为了理解这些机制，我们应用了信息学的方法 研究胸腺基质细胞在年龄相关性萎缩或实验中的转录反应 诱导再生。我们发现，髓质和皮质上皮细胞(TECs)之间的旁分泌信号， 特别是涉及哺乳动物雷帕霉素(MTOR)途径的靶点，可能在 萎缩和再生的机制。开发所需的工具来测试假设mTEC派生的信号 (特别是FGF21)促进胸腺生长，并促进更广泛的旁分泌机制研究 胸腺功能的调节，我们最近发现了一个基因(LPO)，驱动mCherry在胸腺中的特异性表达 胸腺内的mTEC最多。在这里，我们建议产生类似的敲入小鼠，在其中LPO驱动 表达Cre重组酶，允许对mTECs进行组织特异性的基因操作。我们还将使用 利用FGF21LoxP小鼠建立新的模型，研究mTEC来源的FGF21的作用。

Summary T lymphocytes are critical mediators of the adaptive immune response, however, they are continuously lost throughout the lifespan, and therefore must be continuously replaced. The thymus is the primary site of new T cell generation, and the unique thymic stromal microenvironment directs T cell differentiation, self-tolerance and self-restriction. However, the size of the thymus declines precipitously beginning relatively early in life, resulting in declining production of new, naïve T cells. As a result, homeostatic mechanisms driven expansion of memory cells in the periphery, driving a shift toward an oligoclonal T cell memory, leaving the elderly less responsive to vaccines and new infections, especially viral infections. Preventing or reversing age-associated thymic atrophy therefore hold great potential for extending the healthspan in the aging population. The mechanisms governing thymic atrophy have been difficult to identify, because the primary targets of atrophy, cortical thymic stromal cells, are rare and difficult to isolate. To understand these mechanisms, we have applied an informatic approach to characterize the transcriptional response of thymic stromal cells during age-related atrophy or experimentally induced regeneration. We found that paracrine signaling between medullary and cortical epithelial cells (TECs), particularly involving the mammalian target of rapamycin (mTOR) pathway, was likely to play a key role in the mechanisms of atrophy and regeneration. To develop tools required test the hypothesis mTEC-derived signals (particularly FGF21) promote thymus growth, and to facilitate more extensive mechanistic studies of paracrine regulation of thymus function, we recently identified a gene (LPO) that drives specific expression of mCherry in most mTEC within the thymus. Here, we propose the generation of similar knock-in mice in which LPO drives expression of Cre recombinase, allowing tissue-specific genetic manipulation of mTECs. We will also use the newly generated model to investigate the role of mTEC-derived FGF21 using FGF21LoxP mice.