Elucidating the regulation of interleukin-35, a regulatory cytokine, in T cells

阐明 T 细胞中调节性细胞因子 IL-35 的调节

• 批准号: 8432601
• 负责人: Greg M. Delgoffe
• 金额: $ 5.22万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-01 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8432601
• 关键词: Address; Affect; Anti-Inflammatory Agents; Anti-inflammatory; Antigen-Presenting Cells; Antitumor Response; Autoimmune Diseases; Autoimmunity; Binding; Biological Assay; Biology; CD4 Positive T Lymphocytes; Cell Proliferation; Cells; Chronic; Computer Simulation; DNA Methylation; EMSA; Ensure; Epigenetic Process; Equilibrium; Family; Family member; Flow Cytometry; Fluorescence Resonance Energy Transfer; Gene Expression Regulation; Genes; Genetic Transcription; Heterodimerization; Histones; Homeostasis; Homodimerization; Human Herpesvirus 4; Immune; Immune response; Immune system; Immunity; Immunosuppressive Agents; In Vitro; Infection; Interferons; Interleukin Receptor; Interleukin-12; Interleukins; Introns; Kinetics; Lead; Learning; Light; Malignant Neoplasms; Mediating; Mediator of activation protein; Methylation; Modeling; Molecular; Outcome; Pathway interactions; Play; Production; Productivity; Proteins; Regulation; Regulatory T-Lymphocyte; Reporter; Research; Research Proposals; Role; STAT1 gene; STAT4 gene; Signal Pathway; Signal Transduction; Signaling Molecule; Site; T cell regulation; T cell response; T-Cell Proliferation; T-Lymphocyte; Time; Tissues; Work; arm; bisulfite; cell mediated immune response; chromatin immunoprecipitation; cytokine; experience; functional outcomes; in vivo; inhibitor/antagonist; insight; interleukin-23; macrophage; member; novel; pathogen; prevent; promoter; research study; response; success; vector

DESCRIPTION (provided by applicant): The adaptive immune system is an extremely efficient means of eliminating specific pathogens while sparing host tissues. However, this efficiency is dependent on balance; unrestrained immunity can lead to autoimmune disease while a sluggish response can lead to chronic infections and cancer. Regulatory T cells (Tregs) play a critical role in maintaining this balance by suppressing the immune response to self and maintaining immune homeostasis. Tregs utilize many distinct mechanisms to mediate suppression of the immune response. Interleukin-35 (IL-35), a cytokine from the IL-12 family, has emerged as an important soluble mediator of suppression. IL-35 is secreted as a heterodimer of two protein chains, the IL-12 subunit p35 and Epstein-Barr Virus induced gene 3 (Ebi3). IL-35 is a potent inhibitor of immune cell proliferation in vitro and in vivo. Tregs express the genes encoding IL-35 constituitively, while effector T cells do not. However, when naive CD4 T cells are stimulated in the presence of IL-35, they begin to secrete it themselves. Interestingly, the genes encoding p35 and Ebi3 are not generally expressed in T cells; rather, they are utilized by antigen-presenting cells to make cytokines that stimulate the immune response. As such, the regulation of these genes in T cells is still unclear. This research proposal suggests experiments that will propel our understanding of how IL-35 can be regulated in T cells, and elucidate the molecular mechanisms used by IL-35 to mediate suppression of T cell proliferation and conversion to IL-35 producing cells. Understanding these mechanisms is of crucial importance when developing new strategies targeting autoimmunity and cancer.

描述（由申请人提供）：自适应免疫系统是消除特定病原体的一种极为有效的手段，同时保留宿主组织。但是，这种效率取决于平衡。不受约束的免疫力会导致自身免疫性疾病，而缓慢的反应会导致慢性感染和癌症。调节性T细胞（TREG）通过抑制对自我的免疫反应和维持免疫稳态来维持这种平衡起着关键作用。 Treg利用许多不同的机制来介导对免疫反应的抑制。 Iltleukin-35（IL-35）是IL-12家族的细胞因子，已成为重要的抑制介质。 IL-35被分泌为两个蛋白链的异二聚体，IL-12亚基p35和爱泼斯坦 - 巴尔病毒诱导的基因3（EBI3）。 IL-35是体外和体内免疫细胞增殖的有效抑制剂。 Tregs表达编码IL-35的基因 构成型，而效应T细胞没有。但是，当在IL-35存在下刺激幼稚的CD4 T细胞时，它们就开始本身分泌。有趣的是，编码p35和EBI3的基因通常在T细胞中表达。相反，它们被抗原呈递细胞用于制造刺激免疫反应的细胞因子。因此，T细胞中这些基因的调节尚不清楚。这项研究建议提出了实验，可以推动我们对如何在T细胞中调节IL-35的理解，并阐明IL-35用来介导T细胞增殖并转化为IL-35产生细胞的分子机制。在制定针对自身免疫性和癌症的新策略时，了解这些机制至关重要。