The role of paracrine mTOR signaling in regulating thymus size and function

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，特别是流感等病毒感染。防止或逆转与年龄相关的 因此，胸腺萎缩在延长老龄化人口的健康寿命方面具有巨大的潜力。这个 管理胸腺萎缩的机制一直很难确定，因为萎缩的主要目标， 胸腺皮质基质细胞很少见，很难分离。为了理解这些机制，我们应用了 用信息学方法研究胸腺基质细胞在增龄过程中的转录反应 萎缩或实验诱导的再生。在最近发表的一项研究中，我们发现皮质胸腺 上皮细胞(CTECs)表现出独特的形态特征，其特征是广泛的环状突起，而 萎缩与这些突起的收缩有关，这些突起在诱导再生过程中被更新。 此外，我们使用了遗传报告模型和生物合成标记相结合的方法来显示CTEC 数量在萎缩期间不会减少，在再生期间会增加。相反，这些动态过程 似乎受到CTEC大小和分支形态变化的调节。进一步的信息分析表明 延髓和皮质TEC之间的旁分泌信号，特别是涉及哺乳动物靶点 雷帕霉素(MTOR)途径可能在萎缩和再生机制中起关键作用。我们 将通过组织特异性转基因来检验旁分泌mTOR信号维持胸腺大小的假设 小鼠过表达mTOR激活髓质胸腺上皮细胞(MTEC)配体。

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 such as flu. 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. In a recently published study, we showed that cortical thymic epithelial cells (cTECs) display a unique morphology characterized by extensive looping projections, while atrophy is associated with by contraction of these projections, which are renewed during induced regeneration. In addition, we used a combination of genetic reporter models and biosynthetic labeling to show that cTEC numbers do not decrease during atrophy of increase during regeneration. Instead, these dynamic processes appear to be regulated by changes in cTEC size and branching morphology. Further informatic analysis indicated that paracrine signaling between medullary and cortical TEC, particularly involving the mammalian target of rapamycin (mTOR) pathway, was likely to play a key role in the mechanisms of atrophy and regeneration. We will test the hypothesis that paracrine mTOR signaling maintains thymus size using tissue-specific transgenic mice overexpressing mTOR activating ligands in medullary thymic epithelial cells (mTEC).