Balance of Thymic Negative Selection vs. Treg Cell Generation in the Elderly

 描述(申请人提供)：老年人胸腺负向选择与Treg细胞生成的平衡与年龄相关的胸腺退化建立了一种导致老年人慢性炎症(称为炎症老化)的自身免疫易感性。这是由于负选择的缺陷导致自身反应性T的释放增加 细胞。炎症老化显著增加了老年人心血管和神经退行性疾病以及老年癌症的死亡率和发病率。Foxp3+调节性CD4T细胞(Tregs)作为抑制因子，抑制自身反应性T细胞诱导的自身免疫和慢性炎症。尽管老年人通常表现出Tregs在外周的积累而不是减少，但人们很大程度上不知道萎缩的胸腺中的Treg生成是减少还是增加，它是如何与扰动的负选择平衡的，以及它是如何抑制老年外周增加的自我反应性T细胞的。我们假设萎缩的胸腺试图通过增强Treg的生成来平衡缺陷的负选择，以建立老年人的免疫耐受，而Tregs在老年外周的积累可能是平衡增加的自我反应性T细胞的另一种方式。迫切需要在这一领域建立这一知识库，以便有效地控制炎症衰老和年龄相关的自身免疫易感性，从而降低与年龄相关的疾病的风险。为此，我们设计了三个目标来解决这些知识差距。目的1：建立通过增强Treg生成来平衡免疫耐受以弥补老年胸腺负选择缺陷的机制的证据；目的2：确定为什么老年胸腺增强Treg生成不能充分抑制自身反应性T细胞诱导的老年外周炎症衰老；目的3：探索一种潜在的年轻化策略，使用诱导的胸腺上皮样细胞(ITECs)来重新平衡萎缩胸腺中的负选择和Treg生成，并减轻老年外周炎症衰老。在这些研究完成后，将建立一种新的机制，涉及自我反应性T细胞和特异性Treg细胞的平衡，当被破坏时，这将导致与年龄相关的自身免疫易感性和炎症老化。这些机械性的见解将作为开发具有临床意义的恢复异常的年轻化策略的基础 在T细胞免疫系统中的老年人，并减轻自身免疫易感性相关的炎症老化。

 DESCRIPTION (provided by applicant): Balance of Thymic Negative Selection vs. Treg Cell Generation in the Elderly Abstract Age-related thymic involution builds up a predisposition to autoimmunity that contributes to chronic inflammation in the elderly (termed inflamm-aging). This is due to a defect in negative selection which results in increased release of self-reactive T cells. Inflamm-aging significantly increases mortality and morbidity from cardiovascular and neurodegenerative diseases, and late-life cancer in the elderly. FoxP3+ regulatory CD4 T cells (Tregs) act as suppressors to inhibit self-reactive T cell-induced autoimmunity and chronic inflammation. Although aged individuals usually exhibit an accumulation, instead of reduction, of Tregs in the periphery, it is largely unknown whether Treg generation in the atrophied thymus is reduced or enhanced, how it is balanced with perturbed negative selection, and how it suppresses increased self-reactive T cells in the aged periphery. We hypothesize that the atrophied thymus attempts to balance defective negative selection by enhancing Treg generation to establish immune tolerance in aged individuals, and accumulation of Tregs in the aged periphery is probably another way to balance increased self-reactive T cells. There is a critical need to establish this knowledge base in this field in order to efficiently control inflam-aging and age-related autoimmune predisposition, thereby reducing the risk of age-related diseases. To this end, we design three aims to address these knowledge gaps. Aim 1: Establish evidence for the mechanism by which immunotolerance is balanced via enhanced Treg generation to compensate for defects in negative selection in the aged thymus; Aim 2: Determine why enhanced Treg generation in the aged thymus cannot sufficiently suppress self-reactive T cell-induced inflamm-aging in the aged periphery; Aim 3: Explore a potential rejuvenation strategy using induced thymic epithelial-like cells (iTECs) to re-balance negative selection vs. Treg generation in the atrophied thymus and attenuate inflamm-aging in the aged periphery. Upon completion of these studies, a novel mechanism involving a balance of self-reactive T cells vs. specific Treg cells, which when disrupted leads to age-related autoimmune predisposition and inflamm-aging, will be established. These mechanistic insights will serve as a base for the development of clinically significant rejuvenation strategies to restore abnormalities in the T cell immune system in the elderly and attenuate autoimmune predisposition-associated inflamm-aging.