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.

概括 胸腺B细胞最近已显示出表达转录调节剂AIRE，这是Tra的关键介体 小鼠和人类的表达和T细胞耐受性。静脉AIRE的唯一先前已知的来源 表达是髓质上皮细胞（MTEC）的子集。令人惊讶的是，基因队列在转录上 在B和MTEC中，由AIR激活几乎完全不同，表明这些人群可容忍T 细胞到独特的自我抗原人群。在新自我抗原/TCR转基因小鼠模型中，胸腺B细胞为 但是，还显示出对AIRE依赖性自抗原的耐受性，但是，胸腺B细胞介导的作用 中央T细胞耐受性尚未在生理多克隆系统中证明。这部分是由于 与给定自抗原特有的T细胞低频相关的技术困难 多克隆T细胞受体（TCR）曲目，以及胸腺B细胞和MTEC的缺乏。克服这些 要理解施加宽容的机制，需要障碍，以减轻自身免疫性 稳态，尤其是在衰老期间。衰老与许多自身免疫的发病率增加有关 长期以来，疾病和胸腺功能下降一直被认为是与年龄相关的重要贡献者 免疫失调。我们最近的工作表明，小鼠胸腺B细胞中AIR的表达随着年龄的增长而下降 和人类，这将预测会降低对B细胞特异性AIRE依赖性自我抗原的耐受性。 但是，严格测试乳腺功能障碍与T细胞自身免疫性之间的机械联系 之所以受到阻碍，是因为上述技术障碍在老化的，萎缩的 胸腺。我们提出了全面检验的假设，即与年龄相关的TRA表达丧失 胸腺B细胞使用互补方法促进自身免疫性：基于四聚体的T细胞富集 识别内源性TRA和转基因（TG）TCR模型的NEO自我抗原诱导。我们的 模型内源性自身抗原，Titin和载脂蛋白B与迟发性肌无力有关 和动脉粥样硬化，我们还将采用糖尿病TG TCR模型（BDC2.5 TCR TG）。我们 预测老化的胸腺B细胞足以降低T细胞的耐受性，并挽救了TRA表达 在老年细胞中，足以挽救其耐受性的潜力。我们还将全面评估年龄 - TEC和TB细胞从人百里香和TB细胞的相关变化，以比较啮齿动物与年龄相关的变化 人类。这些数据将为防止与年龄相关的策略的合理设计提供信息 自身免疫性，有可能揭示新的治疗靶标。