lymphostromal interactions in the thymic aging

描述（由申请方提供）：衰老导致胸腺退化，这降低了胸腺淋巴细胞生成并耗尽了初始T细胞池，限制了T细胞受体库的多样性并诱导免疫衰老。然而，与胸腺退化相关的细胞区室机制尚不清楚。胸腺中的两个主要细胞区室是淋巴造血祖细胞（LPC）和胸腺上皮细胞（TEC）。目前，它是有争议的，如果LPC开发一个累积的内在缺陷，随着年龄的增长，触发胸腺退化，或是否老化导致功能障碍的TEC，引起继发性变化的胸腺细胞和胸腺退化。基于我们的初步研究，我们假设衰老的主要/主要缺陷是TEC功能障碍，这反过来又导致与年龄相关的胸腺生成功能不全，部分原因是Notch基因信号不足，影响T细胞发育的早期阶段。我们将通过以下具体目标来检验这些假设：1）。比较来自中年/老年和年轻动物的LPC在年轻动物的胸腺基质小生境中竞争性发育的能力。我们将通过来自老年和年轻小鼠的LPC测量未照射的年轻IL-7 R-/-受体胸腺的竞争性再增殖，以确定前者是否具有任何内在的和不可逆的缺陷。我们将使用第二种竞争模型，将来自RAG-/-小鼠的胎儿TEC网络移植到年轻RAG-/-小鼠的肾囊，然后静脉内施用来自老年和年轻小鼠的LPC。2）。确定衰老过程中胸腺微环境是否提供了不足的Notch信号，导致胸腺淋巴细胞生成减少。我们将分析Notch配体在TEC中的表达，以及Notch受体和Notch靶基因在来自老年小鼠的早期胸腺细胞中的表达。然后，我们将通过输注表达Notch配体的胸腺上皮细胞系，在体内向衰老胸腺提供增强的Notch信号传导。然后，我们将确定增强的Notch信号传导是否可以改善老年胸腺中T细胞发育的早期阶段。提出的研究将提高我们对衰老相关的T淋巴细胞生成减少的机制的理解，并为开发实用策略以对抗衰老引起的胸腺生成衰竭奠定基础。公共卫生相关性：该建议将确定具有导致衰老相关胸腺退化的显性/原发性缺陷的细胞室，并确定Notch信号不足是否通过损害老年人早期T细胞发育和T淋巴细胞生成而导致这种缺陷。

DESCRIPTION (provided by applicant): Aging causes thymic involution which decreases thymic lymphopoiesis and exhausts the naive T-cell pool, constricting diversity of T-cell receptor repertoire and inducing immunosenescence. However, the mechanisms related to cellular compartments underlying thymic involution are unclear. The two main cellular compartments in the thymus are lymphohematopoietic progenitor cells (LPCs) and thymic epithelial cells (TECs). Currently, it is controversial if LPCs develop a cumulative intrinsic defect with age to trigger thymic involution, or whether aging results in dysfunction of TECs, causing secondary changes in thymocytes and thymic involution. Based on our preliminary studies, we hypothesize that the primary/dominant defect in aging is dysfunction of TECs, which in turn causes age-related thymopoietic insufficiency, in part through inadequate Notch gene signals that affect early stages of T-cell development. We will test these hypotheses through the following specific aims: 1). Compare the capacity of LPCs from middle-aged/aged and young animals to competitively develop in thymic stromal niches of young animals. We will measure competitive repopulation of unirradiated young IL-7R-/- recipient thymi by LPCs from old and young mice, to determine if the former have any intrinsic and irreversible defects. We will use a second competitive model, transplanting a fetal TEC network from RAG-/- mice to the kidney capsule of young RAG-/- mice, followed by intravenous administration of LPCs from old and young mice. 2). To determine whether the thymic microenvironment in aging provides inadequate Notch signals, resulting in reduced thymic lymphopoiesis. We will analyze expression of Notch ligands in TECs, and Notch receptors and Notch target genes in early stage thymocytes from aged mice. Then, we will provide enhanced Notch signaling to aged thymus in vivo by infusing Notch ligand-expressing thymic epithelial cell lines. We will then determine whether the enhanced Notch signaling can improve early stages of T-cell development in the aged thymus. The proposed studies will improve our understanding of the mechanism(s) of aging-related decreased T-lymphopoiesis and lay the groundwork for development of practical strategies to combat thymopoietic failure due to aging. PUBLIC HEALTH RELEVANCE: This proposal will identify the cellular compartment which has the dominant/primary defect that causes aging-related thymic involution, and determine whether inadequate Notch signals contribute to this defect by impairing early T-cell development and T-lymphopoiesis in the elderly.