Autoreactive CD4 T cells in healthy mice

健康小鼠的自身反应性 CD4 T 细胞

• 批准号: 10621383
• 负责人: LESZEK IGNATOWICZ
• 金额: $ 39万
• 依托单位: GEORGIA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10621383
• 关键词: Ablation; Acceleration; Agonist; Antigen Receptors; Antigen-Presenting Cells; Autoantigens; Autoimmune Diseases; Autoimmunity; Bar Codes; Binding; Bypass; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cells; Chromatin; Development; Devices; Diphtheria Toxin; Disabled Persons; Epigenetic Process; Gene Targeting; Genomics; Homeostasis; Human; Immune response; Individual; Infection; MHC Class I Genes; MHC Class II Genes; Maintenance; Malignant Neoplasms; Microfluidics; Modeling; Mus; Organ; Pathogenicity; Peptides; Peripheral; Protocols documentation; Receptor Activation; Receptor Cell; Regulatory T-Lymphocyte; Reproducibility; Research; Rest; Role; Self Tolerance; Specificity; Stromal Cells; System; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Therapeutic; Thymus Gland; Tissues; Transposase; Visit; autoreactive T cell; autoreactivity; central tolerance; high throughput analysis; lymphoid organ; novel therapeutics; peripheral tolerance; prevent; reconstruction; response; single-cell RNA sequencing; thymocyte; transcriptome

In the thymus, central tolerance should eliminate the majority of immature T cells that express autoreactive, pathogenic antigen receptors (αβTCRs). However, an unknown number of autoreactive cells escape deletion or commit to immunosuppressive, regulatory linage (Tregs). Tregs control peripheral tolerance and sustain dormancy of potentially autoreactive T cells. However, mice and humans with disabled Tregs rapidly develop multiorgan autoimmunity and die young, manifesting polyclonal activation of almost all CD4+ clones. Thus, we hypothesized that the number of autoreactive clones embedded in the peripheral repertoire can be much higher (i.e. over one-third of all CD4+ cells) as compared to what is currently anticipated. In Specific Aim 1, we will examine how the intrathymic expression of different self-peptides supports or prevents an escape of autoreactive T cells from central tolerance. This approach will document that potentially self-reactive CD4+ clones commonly trespass to lymphoid organs of B6 mice as quiescent cells. Next, we will test these cells ex vivo responses to a known set of self-peptides naturally presented by mouse Ab molecules to determine if these clones are triggered by ubiquitous or specific autoantigens. In Specific Aim 2, we will investigate why mice expressing single autoantigen across the body have main autoimmunity manifestation in specific organs and examine the role of non-classical CD4+ T cells in autoimmunity in this model. In Aim 3 we will use a new single-cell RNA seq system from 10X Genomics, to examine in individual CD4+ cells their transcriptomes and native αβTCRs to identify genes targeted by Tregs in potentially autoreactive cells to keep them dormant and prevent autoimmunity. Overall, this application will revisit the relative importance of various mechanisms of tolerance in the maintenance of homeostasis to self- antigens and can reveal new mechanisms of how Tregs control self-reactivity.

在胸腺中，中央耐受性消除了大多数未成熟的ttters 表达自动反应性，致病性抗原受体（αβTCR）。 自动反应性细胞逃脱了划界或社区，以进行免疫抑制，调节外线（Tregs）。 Tregs控制毒T细胞的外周耐受性和可持续性。 霍弗（Howver），老鼠和患有残疾treg的人迅速发展多机器人自身免疫性并死亡 年轻的，几乎所有CD4+克隆的多克隆激活。 嵌入在外围曲目中的自动反应性克隆数量可能会更大（即 与当前预期的AM 1相比，所有CD4+细胞的三分之一以上。 我们将研究不同自肽的胸膜表达如何倡导或阻止 自动反应性T细胞从中央耐受性中逃脱。 自反应的CD4+克隆通常会侵入B6小鼠的淋巴器官作为静止细胞。 接下来，我们将测试这些细胞对一组自然呈现的已知自肽的反应 通过小鼠AB分子来确定这些克隆是否被普遍或特定触发 自动抗原。 整个身体在特定器官中具有主要的自身免疫性表现，并检查角色 在此模型3中的自身免疫中的非经典CD4+ T细胞。 从10倍基因组学的RNA SEQ系统，用于在单个CD4+细胞中检查其转录。 和天然的αβTCR，以鉴定Treg在潜在自身反应性细胞中靶向的基因以保持 主题和防止自身免疫。 各种宽容机制在维持体内平衡方面的重要性 抗原和可以启用Treg如何控制自我反应性的新机制。