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

老年人胸腺负选择与 Treg 细胞生成的平衡

• 批准号: 9003334
• 负责人: DONG-MING SU
• 金额: $ 35.35万
• 依托单位: UNIVERSITY OF NORTH TEXAS HLTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-12-01 至 2020-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9003334
• 关键词: Address; Affect; Affinity; Aging; Animals; Antigens; Apoptotic; Atrophic; Attenuated; Autoantigens; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Binding; CD4 Positive T Lymphocytes; Cardiovascular Diseases; Cells; Chronic; Defect; Development; Disease; Elderly; Embryo; Epithelial; Equilibrium; Exhibits; Experimental Autoimmune Encephalomyelitis; Family member; Fibroblasts; Functional disorder; Generations; Genes; Goals; Human; Immune; Immune Tolerance; Immune system; Incidence; Individual; Inflammation; Inflammatory; Knock-out; Knowledge; Malignant Neoplasms; Morbidity - disease rate; Multiple Sclerosis; Mus; Myelin Basic Proteins; Neurodegenerative Disorders; Outcome; Output; Peptide/MHC Complex; Peptides; Peripheral; Predisposition; Process; Production; Public Health; Publishing; Receptor Activation; Regulatory T-Lymphocyte; Rejuvenation; Reporting; Research; Risk; Role; T-Lymphocyte; Techniques; Testing; Thymus Gland; Time; Transgenic Mice; Uveitis; abstracting; acronyms; age related; aged; base; clinically significant; design; imprint; insight; interstitial retinol-binding protein; knowledge base; mortality; mouse model; novel; overexpression; prevent; public health relevance; research study; thymocyte

 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.

 描述（由申请人提供）：老年人胸腺负选择与Treg细胞生成的平衡摘要与年龄相关的胸腺退化会增加自身免疫的倾向，从而导致老年人的慢性炎症（称为炎症老化）。这是由于负选择的缺陷，导致自身反应性T细胞的释放增加。 细胞炎症老化显著增加老年人心血管和神经退行性疾病以及晚期癌症的死亡率和发病率。FoxP 3+调节性CD 4 T细胞（TCR 4）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。尽管老年个体通常表现出外周中T细胞的积累，而不是减少，但在很大程度上不知道萎缩胸腺中Treg的产生是减少还是增强，它如何与干扰的负选择平衡，以及它如何抑制老年外周中增加的自身反应性T细胞。我们假设萎缩的胸腺试图通过增强Treg的产生来平衡有缺陷的负选择，以在老年个体中建立免疫耐受，并且TdR在老年外周中的积累可能是平衡增加的自身反应性T细胞的另一种方式。迫切需要在这一领域建立这种知识基础，以有效地控制炎症-衰老和年龄相关的自身免疫易感性，从而降低年龄相关疾病的风险。为此，我们设计了三个目标来解决这些知识差距。目标1：建立通过增强的Treg生成来平衡免疫耐受以补偿老年胸腺中负选择缺陷的机制的证据;目的2：确定为什么老年胸腺中增强的Treg生成不能充分抑制老年外周中自身反应性T细胞诱导的炎症-衰老;目的3：探索使用诱导的胸腺上皮样细胞（iTEC）重新平衡萎缩胸腺中的阴性选择与Treg生成并减轻老年外周中的炎症老化的潜在复壮策略。在完成这些研究后，将建立一种涉及自身反应性T细胞与特异性Treg细胞平衡的新机制，这种机制在被破坏时会导致年龄相关的自身免疫易感性和炎症老化。这些机制的见解将作为一个基础，为临床显着的振兴战略，以恢复异常的发展 在老年人的T细胞免疫系统和减弱自身免疫易感性相关的炎症老化。