Mechanisms maintaining the self-awareness of peripheral T cells

维持外周T细胞自我意识的机制

• 批准号: 9979091
• 负责人: Nevil John Singh
• 金额: $ 19.31万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-20 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9979091
• 关键词: Ablation; Affect; Antigens; Autoantigens; Autoimmune Diseases; Autoimmunity; Automobile Driving; Awareness; Biochemical; Biochemical Pathway; Biological; Categories; Cell Compartmentation; Cell physiology; Cells; Complex; Dangerousness; Data; Development; Drug Targeting; Ensure; Future; Gene Expression; Genes; Genetic; Heterogeneity; I Kappa B-Alpha; Immune response; Immune system; Immunity; Immunotherapy; Infectious Agent; Knockout Mice; Lead; Ligands; Link; Literature; Maintenance; Mature T-Lymphocyte; Mediating; Membrane Glycoproteins; Memory; Modeling; Molecular; NF-kappa B; Pathogenicity; Pathway interactions; Peptide/MHC Complex; Peptides; Peripheral; Pharmacology; Process; Proteins; Receptor Signaling; Reporting; Rest; Risk; Self Perception; Seminal; Series; Signal Pathway; Signal Transduction; Signaling Molecule; Surrogate Markers; T cell response; T-Cell Activation; T-Cell Development; T-Cell Receptor; T-Lymphocyte; Testing; Thymus Gland; Transgenic Organisms; Up-Regulation; Vaccine Design; Vaccines; Variant; autoreactive T cell; base; conditional knockout; design; experimental study; fighting; improved; insight; pathogen; response; theories; thymocyte; translational approach; vaccine efficacy

Summary: Mechanisms maintaining the self-awareness of peripheral T cells The ability of T cells in our peripheral immune system to robustly respond when stimulated by their antigen is highly desirable in the context of repelling attacks by dangerous pathogens. In contrast, strong T cell responses to self-antigens would be pathogenic, leading to autoimmune disease. Therefore, as a central tenet of the clonal selection theory, the immune system is expected to eliminate strongly autoreactive T cells during development in the thymus and dampen the remaining self-reactivity by peripheral mechanisms. In this context, it is surprising that all T cells undergo positive selection on self-peptides in the thymus – ensuring that they are all at least nominally self-reactive. After positive selection a series of TCR-proximal tuning mechanisms, including the upregulation of a cell-surface glycoprotein CD5, ensures that this self-reactivity is not pathogenic. In recent years it is increasingly clear that despite such tuning, peripheral T cells not only continue to be aware of their self-ligands but also use this self-awareness to promote responses to pathogens. The mechanisms of these linked processes are not fully understood. Based on our preliminary studies, we propose that biochemical signals downstream of CD5 itself help to promote the preferential activation and survival of better self-aware T cells in the peripheral Immune system. Here, we propose to use CD5-conditional-knockout mice and infectious challenges to test this hypothesis. The significance of these studies is that it is expected to provide a more comprehensive model for how self-recognition synergizes with pathogen-specific responses in the T cell compartment. The insights gained from these studies can lead to future translational approaches improving the design of vaccines as well as informing the selection and design of T cell transfer therapies.

维持外周T细胞自我意识的机制 我们的外周免疫系统中的T细胞在受到刺激时强烈反应的能力 它们的抗原在抵抗危险病原体攻击的情况下是非常需要的。在 相反，T细胞对自身抗原的强烈反应将是致病的，导致自身免疫性疾病。 疾病因此，作为克隆选择理论的中心原则，免疫系统是 预期在胸腺发育过程中消除强烈的自身反应性T细胞， 通过外围机制来维持剩余的自我反应性。在这种情况下，令人惊讶的是，所有的T 细胞在胸腺中对自身肽进行正选择-确保它们都至少 名义上是自反应的经过一系列TCR近端调节机制的阳性选择后， 包括细胞表面糖蛋白CD 5的上调，确保了这种自身反应性， 不是致病的近年来，越来越清楚的是，尽管有这样的调节，外周T细胞 不仅继续意识到他们的自我配体，而且还利用这种自我意识来促进 对病原体的反应。这些相互关联的过程的机制尚未完全了解。 基于我们的初步研究，我们提出CD 5自身下游的生化信号 有助于促进外周血中更好的自我意识T细胞的优先激活和存活 免疫系统在这里，我们建议使用CD 5-条件敲除小鼠和感染性 挑战来检验这个假设。这些研究的意义在于， 自我识别如何与病原体特异性协同作用的更全面的模型 T细胞区室中的反应。从这些研究中获得的见解可以导致未来 翻译方法改进疫苗的设计以及告知选择和 设计T细胞转移疗法。