Causes and consequences of declining B cell-mediated central T cell tolerance throughout the lifespan

B 细胞介导的中枢 T 细胞耐受性在整个生命周期中下降的原因和后果

• 批准号: 10393822
• 负责人: Ann Venables Griffith
• 金额: $ 26.34万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10393822
• 关键词: Ablation; Address; Adoptive Transfer; Age; Aging; Animals; Antibodies; Apolipoprotein E; Apolipoproteins B; Apoptosis; Atherosclerosis; Atrophic; Autoantigens; Autoimmune; Autoimmune Diseases; Autoimmunity; B-Lymphocytes; Bone Marrow Transplantation; Cell physiology; Cell surface; Cells; Clonal Deletion; Data; Diabetes Mellitus; Epithelial Cells; Frequencies; Functional disorder; Gene Expression; Genes; Genetic Transcription; Human; Immune; Incidence; Kinetics; Lesion; Link; Longevity; LoxP-flanked allele; Lymphocytic Infiltrate; Maps; Measures; Mediating; Mediator of activation protein; Modeling; Mus; Myasthenia Gravis; Outcome; Peptides; Peripheral; Phenotype; Physiological; Population; Publishing; Recombinants; Regulatory T-Lymphocyte; Research; Rodent; Role; Self Tolerance; Signal Transduction; Source; System; T-Cell Receptor; T-Lymphocyte; T-cell receptor repertoire; TNFRSF5 gene; TNFSF11 gene; Testing; Thymic Tissue; Thymic epithelial cell; Thymus Gland; Tissue Model; Tissues; Transgenic Mice; Transgenic Organisms; Transplantation; Work; age effect; aged; base; cell age; cohort; connectin; design; humoral immunity deficiency; immune function; mouse model; new therapeutic target; novel; overexpression; peripheral blood; prevent; secondary lymphoid organ; transcriptome; transcriptome sequencing

Summary Thymic B cells have recently been shown to express the transcriptional regulator Aire, a critical mediator of TRA expression and T cell tolerance in mice and humans. The only previously known source of intrathymic Aire expression was a subset of medullary epithelial cells (mTECs). Surprisingly, the cohort of genes transcriptionally activated by Aire are almost entirely distinct among B and mTEC, indicating that these populations tolerize T cells to unique cohorts of self-antigens. In a neo-self-antigen/TCR transgenic mouse model, thymic B cells were also shown to mediate tolerance to Aire-dependent self-antigens, however, the role of thymic B cell-mediated central T cell tolerance has not been demonstrated in a physiologically polyclonal system. This is in part due to the technical difficulties associated with the low frequency of T cells specific for a given self-antigen in a polyclonal T cell receptor (TCR) repertoire, and the paucity of thymic B cells and mTECs. Overcoming these obstacles is necessary to understand the mechanisms imposing tolerance to mitigate autoimmunity both in the steady state, and especially during aging. Aging is associated with increased incidence of many autoimmune diseases, and declining thymus function has long been considered an important contributor to age-associated immune dysregulation. Our recent work revealed that Aire expression declines with age in thymic B cells in mice and humans, which would be predicted to diminish tolerance to B cell-specific Aire-dependent self-antigens. However, rigorously testing the mechanistic link between thymic dysfunction and T cell autoimmunity in aging has been hindered because the technical barriers described above are exacerbated in the aged, atrophied thymus. We propose comprehensively testing the hypothesis that age-associated loss of TRA expression in thymic B cells promotes autoimmunity using complementary approaches: tetramer-based enrichment of T cells recognizing endogenous TRAs, and transgenic (Tg) TCR models of tolerance induction to neo self-antigens. Our model endogenous autoantigens, Titin, and Apolipoprotein B, are associated with late-onset Myasthenia Gravis and atherosclerosis, respectively, and we will also employ a Tg TCR model of diabetes (BDC2.5 TCR Tg). We predict that aged thymic B cells will be sufficient to diminish T cell tolerance, and that rescued TRA expression in aged cells will be sufficient to rescue their tolerization potential. We will also comprehensively assess age- associated changes in TEC and tB cells from human thymi to compare age-associated changes in rodents and humans. Together, these data will inform the rational design of strategies to prevent age-associated autoimmunity, potentially revealing novel therapeutic targets.

摘要 最近发现胸腺B细胞表达转录调节因子Aire，它是TRA的关键介质 T细胞在小鼠和人体内的表达和耐受性。之前已知的胸腺内Aire的唯一来源 表达为髓上皮细胞(MTECs)的一部分。令人惊讶的是，这组基因在转录上 由Aire激活的B和mTEC几乎完全不同，表明这些种群对T 细胞与独特的自身抗原队列相结合。在新自身抗原/TCR转基因小鼠模型中，胸腺B细胞 也显示介导对Aire依赖的自身抗原的耐受性，然而，胸腺B细胞介导的作用 中枢性T细胞耐受性在生理学多克隆系统中尚未得到证实。这部分归因于 与低频率的针对给定自身抗原的T细胞相关的技术困难 多克隆T细胞受体(TCR)谱系，以及胸腺B细胞和mTECs的缺乏。克服这些障碍 障碍是理解施加耐受以减轻自身免疫的机制所必需的，在 处于稳定状态，尤其是在老化过程中。衰老与许多自身免疫性疾病的发病率增加有关 疾病和胸腺功能下降一直被认为是与年龄相关的重要因素 免疫失调。我们最近的工作表明，Aire在小鼠胸腺B细胞中的表达随着年龄的增长而下降 以及人类，据预测，这将降低对B细胞特异性Aire依赖自身抗原的耐受性。 然而，严格测试胸腺功能障碍和衰老中T细胞自身免疫之间的机制联系 受到阻碍，因为上述技术壁垒在老年人中加剧，萎缩 胸腺。我们建议全面检验这一假设，即与年龄相关的TRA表达缺失在 胸腺B细胞通过互补途径促进自身免疫：基于四聚体的T细胞浓缩 识别内源性TRAS和转基因(TG)TCR模型诱导对neo自身抗原的耐受。我们的 模型内源性自身抗原、肌动蛋白和载脂蛋白B与迟发性重症肌无力相关 我们还将采用糖尿病的TG-TCR模型(BDC2.5-TCR-TG)。我们 预测老化的胸腺B细胞将足以降低T细胞的耐受性，并挽救TRA的表达 在老化的细胞中将足以挽救其耐受潜力。我们还将全面评估年龄- 人胸腺TEC和TB细胞的相关变化以比较啮齿动物和 人类。总而言之，这些数据将为合理设计预防年龄相关性疾病的策略提供信息 自身免疫，可能揭示新的治疗靶点。