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.

CD4+辅助T细胞目前至少分化为五个定义明确的子集：Th0，Th1，Th2，Treg，Th17和T卵泡辅助器，可以促进和抑制彼此的行为。淋巴因子IL-15是重要的IL-2相关细胞因子，其在辅助子集分化和增殖中的作用尚未完全阐明。在这项研究中，我们表明，外源IL-15在Th17区分培养物中降低了IL-17A的产生。 IL-15的中和导致Th17培养物的IL-17A产生增加。与野生型（WT）细胞相比，上清液中IL15（ - / - ）和IL15R（ - / - ）T细胞培养物在上清液中均显示出更高的IL-17A生产者和较高量的IL-17a。 IL-15下调的IL-17A产生与视黄酸相关的孤儿受体-γT，FOXP3和IFN-γ表达无关。 Th17细胞和APC均产生IL-15，这诱导了STAT5的结合，STAT5是CD4 T细胞中IL17基因座的明显抑制剂。同样，在髓磷脂少突胶质细胞糖蛋白诱导的自身免疫性脑脊髓炎（EAE）的模型中，IL15（ - / - ）小鼠表现出随着其CD4（+）T细胞的产生而增加的IL-17A产生的炎症 - 炎症 - 炎症 - 炎症 - 炎症 - 炎症，并由其CD4（+）T细胞与WT对照组合在一起。外源性IL-15给药和IL-17A中和降低了IL15（ - / - ）小鼠中EAE的严重程度。综上所述，这些数据表明IL-15在IL-17A产生和Th17介导的炎症中具有负调节作用。