MicroRNAs as T cell sensitivity Rheostats

MicroRNA 作为 T 细胞敏感性变阻器

• 批准号: 7802920
• 负责人: CHANG-ZHENG CHEN
• 金额: $ 40.12万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7802920
• 关键词: Address; Affect; Affinity; Agonist; Animals; Antigens; Autoantigens; Autoimmune Diabetes; Autoimmune Diseases; B-Cell Development; Cells; Development; Down-Regulation; Ectopic Expression; Ensure; Family member; Gene Family; Genes; Genetic; Immune response; Immunity; In Vitro; Lead; Ligands; Lymphocyte; Maintenance; Malignant Neoplasms; Mature T-Lymphocyte; MicroRNAs; Molecular; Multiple Sclerosis; Mus; Notch Signaling Pathway; Nucleotides; Pathogenesis; Peptide/MHC Complex; Peptides; Peripheral; Play; Population; Regulation; Research; Rheumatoid Arthritis; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Systemic Lupus Erythematosus; T cell regulation; T memory cell; T-Cell Development; T-Cell Receptor; T-Lymphocyte; TCR Activation; Testing; Thymus Gland; Untranslated RNA; central tolerance; experience; in vivo; insight; knock-down; loss of function; notch protein; public health relevance; thymocyte

DESCRIPTION (provided by applicant): T cell sensitivity to antigens is intrinsically regulated during lymphocyte development and maturation to ensure proper development of immunity and tolerance, but how this is accomplished remains elusive. MicroRNAs (miRNAs), an abundant class of ~22-nucleotide (nt) small noncoding RNAs, have emerged as important players in animal development, the pathogenesis of cancers, and immune responses. Among them, miR-181a is preferentially expressed during lymphocyte development and plays important roles in T and B cell development. Increasing miR-181a expression in mature T cells augments the sensitivity to peptide antigens, whereas inhibiting miR-181a expression in immature T cells reduces sensitivity and impairs both positive and negative selection. Interestingly, quantitative regulation of T cell sensitivity by miR-181a enables mature T cells to recognize antagonists--the inhibitory peptide antigens--as agonists, suggesting that quantitative regulation of antigen sensitivity could result in a shift in the activation threshold in T cells. Supporting the idea that miR-181a may function as an intrinsic antigen-sensitivity `rheostat' during T cell development is that higher miR-181a expression seems to correlate with greater T cell sensitivity in various T cell populations. The proposed research plan will examine the function of the mir-181 family genes in regulating T cell sensitivity to antigens during lymphocyte development, selection, and function, and will further test the effects of tuning miRNA expression on the development of tolerance. Specifically, we will use loss-of-function approaches, including pharmacological (antagomir knock-down) and genetic (targeted deletions in mice) approaches, to reduce or abrogate the expression of the mir-181 family genes in DP cells, in order to determine the roles these miRNA genes play in controlling TCR signaling strength in DP thymocytes and in influencing positive and negative selection (Specific Aim 1). We will also characterize the roles of the mir-181 family genes in the development of the peripheral T cell receptor repertoire as well as naive and memory T cells (Specific Aim 2). Finally, we will investigate the functions of the mir-181 family genes in early T cell development in the thymus by controlling the pre-TCR and Notch signaling pathways (Specific Aim 3). PUBLIC HEALTH RELEVANCE: The proposed study will provide fundamental insight as to how aberrant miRNA expression may contribute to the pathogeneses of autoimmune diseases, such as systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, and type-1 autoimmune diabetes.

描述（由申请人提供）：T细胞对抗原的敏感性在淋巴细胞发育和成熟过程中本质上受到调节，以确保免疫和耐受性的适当发展，但是如何实现这一目标仍然难以捉摸。 MicroRNA（miRNA）是大量的〜22-核苷酸（NT）小型非编码RNA，已经成为动物发育，癌症发病机理和免疫反应的重要参与者。其中，miR-181a在淋巴细胞发育过程中优先表达，并在T和B细胞发育中起重要作用。成熟T细胞中的miR-181a表达增加增强对肽抗原的敏感性，而抑制未成熟T细胞中的miR-181a表达会降低敏感性并损害阳性和阴性选择。有趣的是，miR-181a对T细胞敏感性的定量调节使成熟的T细胞能够识别拮抗剂（作为激动剂的抑制性肽抗原），这表明对抗原敏感性的定量调节可能会导致T细胞激活阈值的转移。支持miR-181a在T细胞发育过程中可能起到固有的抗原敏感性“风湿病”的想法是，较高的miR-181a表达似乎与各种T细胞群体中的T细胞灵敏度较高相关。拟议的研究计划将检查miR-181家族基因在调节淋巴细胞发育，选择和功能过程中调节T细胞对抗原的敏感性的功能，并将进一步测试MiRNA表达对耐受性发展的影响。具体而言，我们将使用功能丧失方法，包括药理学（Antagomir敲除）和遗传方法（小鼠中的靶向缺失）方法，以减少或废除DP细胞中miR-181家族基因的表达，以确定这些miRNA在控制DP胸腺细胞中的TCR信号强度和负面影响（在选择）中的作用（这些miRNA）在选择性和选择（在选择性方面）。我们还将表征miR-181家族基因在周围T细胞受体库以及幼稚和记忆T细胞发展中的作用（特定AIM 2）。最后，我们将通过控制TCR和Notch信号通路（特定的AIM 3）来研究miR-181家族基因在胸腺早期T细胞发育中的功能。公共卫生相关性：拟议的研究将为异常miRNA表达如何促进自身免疫性疾病的病原体，例如全身性红斑狼疮，类风湿关节炎，多发性硬化症和1型自身免疫性糖尿病。