Stromal catalase deficiency as the causative factor in accelerated thymic atrophy

描述(申请人提供)：像所有的血细胞一样，T淋巴细胞在一生中不断丢失，必须不断地更换。胸腺是T淋巴细胞生成的主要部位。然而，胸腺的特点是加速的、与年龄相关的萎缩，导致新的(自然)T淋巴细胞产量随着年龄的增长而逐渐下降。尽管预先存在的T淋巴细胞的复制可以防止淋巴细胞减少的出现，但这些T细胞大多是记忆T细胞。因此，应对新的免疫挑战的能力，如新出现的病毒株，随着年龄的增长而下降，对疫苗接种的反应也是如此。胸腺加速衰老的机制尚未得到很好的解决，但现在清楚的是，它主要是一种间质表型。我们最近发表了一种新的方法来表征胸腺基质基因的原位表达，提供了一个前所未有的间质生物学的视角，并揭示了许多关于它们的本质的见解。一个意想不到的发现是，胸腺基质细胞缺乏关键酶，这些酶参与保护免受活性氧物种(ROS)造成的损伤，以及几种修复这种损伤的酶。最值得注意的是，胸腺基质细胞似乎严重缺乏过氧化氢酶，过氧化氢酶是过氧化氢的主要清除剂。由于胸腺基质细胞的寿命相对较长，并且存在于以强烈代谢活动为特征的微环境中(与淋巴母细胞增殖相关)，因此在保护/修复ROS损伤方面的缺陷可能会导致功能、活力和复制能力的加速下降，并出现萎缩。我们的中心假设是，由于这些酶的缺乏，胸腺上皮基质细胞对ROS非常敏感，胸腺萎缩是代谢损伤加速积累的结果。在这一应用中，我们提供了强大的生化和遗传学数据来支持这一假说，并提出了进一步证明这一假说的实验，包括显示过氧化氢酶的基因替代特定于上皮细胞 胸腺基质足以防止萎缩，胸腺上皮基质细胞比其他年龄和/或谱系匹配的细胞在体内积累更多的损伤，分离的胸腺上皮细胞比其他年龄和/或谱系匹配的细胞对ROS更敏感，修复机制的缺陷加剧了胸腺上皮细胞过氧化氢酶缺乏的后果。这些研究有望揭示胸腺加速萎缩的机制，并可能提出减少或预防这种病理状态的方法。

DESCRIPTION (provided by applicant): Like all blood cells, T lymphocytes are constantly lost during life, and must be continuously replaced. The thymus is the primary site of T lymphopoiesis. However, the thymus is characterized by an accelerated, age-related atrophy, leading to a progressive decline in new (na¿ve) T lymphocyte production with age. Although replication of pre-existing T lymphocytes prevents the appearance of lymphopenia, these are mostly memory T cells. Consequently, the ability to respond to new immunological challenges, such as emerging viral strains, decreases with age, as does response to vaccination. The mechanisms for accelerated thymic aging are not well resolved, but it is now clear that it is primarily a stromal phenotype. We have recently published a novel approach for the characterization of thymic stromal gene expression in situ, providing an unprecedented view of stromal biology, and revealing many insights into their nature. One unexpected finding was that thymic stromal cells are deficient in key enzymes involved in protection from damage caused by reactive oxygen species (ROS), as well as several enzymes that repair that damage. Most notably, thymic stromal cells appear to be profoundly deficient in catalase, a major scavenger of H2O2. Since thymic stromal cells are relatively long-lived, and exist in a microenvironment characterized by intense metabolic activity (associated with lymphoblastic progenitor proliferation), defects in protection from / repair of ROS damage would be expected to result in an accelerated decline in function, viability, and replicative ability, and the appearance of atrophy. Our central hypothesis is that epithelial stromal cells of the thymus are exquisitely sensitive to ROS by virtue of these enzyme deficiencies, and that thymic atrophy is a consequence of accelerated accumulation of metabolic damage. In this application, we present powerful biochemical and genetic data to support this hypothesis, and propose experiments to further prove it, including showing that genetic replacement of catalase specifically in epithelial stroma of the thymus is sufficient to prevent atrophy, that epithelial stromal cells of the thymus accumulate more damage in vivo than other age- and/or lineage-matched cells, that isolated thymic epithelial cells are more sensitive to ROS than other age- and/or lineage-matched cells, and that deficiencies in repair mechanisms exacerbate the consequences of catalase deficiency in thymic epithelial cells. These studies are expected to reveal the mechanism of accelerated thymic atrophy, and may suggest approaches to reduce or prevent this pathological state.