GENE REGULATORY EVENTS IN ESTABLISHING MATURE T CELL TOLERANCE

建立成熟 T 细胞耐受性的基因调控事件

• 批准号: 8745315
• 负责人: michael j lenardo
• 金额: $ 55.86万
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8745315
• 关键词: Apoptosis; Autoimmune Process; Behavior; Binding; CD4 Positive T Lymphocytes; Cell Culture Techniques; Cells; Characteristics; Data; Event; Experimental Autoimmune Encephalomyelitis; Frequencies; Goals; Helper-Inducer T-Lymphocyte; Immune; Immune system; In Vitro; Inflammation; Interferons; Interleukin-15; Interleukin-17; Interleukin-2; Lymphokines; Mature T-Lymphocyte; Mediating; Modeling; Molecular; Mus; Organ; Orphan; Physiological; Process; Production; Regulation; Regulator Genes; Regulatory T-Lymphocyte; Research; Role; STAT5A gene; Severities; T-Lymphocyte; T-Lymphocyte Subsets; Time; Tretinoin; Work; anergy; cell type; cytokine; oligodendrocyte-myelin glycoprotein; receptor

CD4+ helper T-cell differentiate into at this time at least five well-defined subsets: Th0, Th1, Th2, Treg, Th17, and T follicular helper that can both promote and inhibit the behavior of each other. The lymphokine IL-15 is an important IL-2-related cytokine whose role in helper subset differentiation and proliferation has not been fully elucidated. In this study, we show that exogenous IL-15 decreased IL-17A production in Th17 differentiating cultures. Neutralization of IL-15 led to increases in IL-17A production in Th17 cultures. Both Il15(-/-) and Il15r(-/-) T cell cultures displayed higher frequency of IL-17A producers and higher amounts of IL-17A in the supernatants compared with those of wild-type (WT) cells in vitro. IL-15 down-modulated IL-17A production independently of retinoic acid-related orphan receptor-γt, Foxp3, and IFN-γ expression. Both Th17 cells and APCs produced IL-15, which induced binding of STAT5, an apparent repressor to the Il17 locus in CD4 T cells. Also, in a model of myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis (EAE), Il15(-/-) mice displayed exacerbated inflammation-correlating with increased IL-17A production by their CD4(+) T cells-compared with WT controls. Exogenous IL-15 administration and IL-17A neutralization reduced the severity of EAE in Il15(-/-) mice. Taken together, these data indicate that IL-15 has a negative regulatory role for IL-17A production and Th17-mediated inflammation.

目前，CD4+辅助性T细胞至少分化为5个亚群：Th0、Th1、Th2、Treg、Th17和T滤泡辅助性T细胞，它们可以促进和抑制彼此的行为。淋巴因子IL-15是一种重要的IL-2相关细胞因子，其在辅助细胞亚群分化和增殖中的作用尚未完全阐明。在这项研究中，我们发现外源IL-15减少了Th17分化培养物中IL-17A的产生。IL-15的中和导致Th17细胞产生IL-17A的增加。与野生型(WT)细胞相比，IL15(-/-)和IL15R(-/-)T细胞培养物产生IL-17A的频率和培养上清液中IL-17A的含量都较高。IL-15下调IL-17A的产生，不依赖于维甲酸相关的孤儿受体、Foxp3和干扰素的表达。Th17细胞和APC都产生IL-15，从而诱导STAT5与CD4T细胞中IL17位点的明显抑制物结合。此外，在髓鞘少突胶质细胞糖蛋白诱导的实验性自身免疫性脑脊髓炎(EAE)模型中，与WT对照组相比，IL15(-/-)小鼠表现出炎症加剧-与其CD4(+)T细胞产生的IL-17A增加有关。外源性IL-15应用和IL-17A中和可降低IL15(-/-)小鼠的EAE严重程度。综上所述，这些数据表明，IL-15对IL-17A的产生和Th17介导的炎症具有负面调节作用。