Regulation of T helper cell effector function

T辅助细胞效应功能的调节

• 批准号: 8894193
• 负责人: Xuexian Yang
• 金额: $ 36.48万
• 依托单位: UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8894193
• 关键词: Autoimmune Diseases; Autoimmune Process; Biological Assay; CD4 Positive T Lymphocytes; Categories; Cell Differentiation process; Cell physiology; Cells; Co-Immunoprecipitations; Critical Pathways; Cytoplasmic Granules; Data; Defect; Development; Enzyme-Linked Immunosorbent Assay; Experimental Autoimmune Encephalomyelitis; Extrinsic asthma; Flow Cytometry; Genetic Transcription; Health; Helper-Inducer T-Lymphocyte; Human; Immune response; In Vitro; Membrane; Messenger RNA; Modeling; Molecular; Mus; Pathway interactions; Play; Point Mutation; Production; Protein Binding; Protein Deficiency; Proteins; RNA; RNA Stability; RNA-Binding Proteins; Regulation; Reporter; Repression; Reverse Transcriptase Polymerase Chain Reaction; Role; Secretory Cell; Specific qualifier value; Stress; Syndrome; System; Systemic Lupus Erythematosus; T-Lymphocyte; Therapeutic; Ursidae Family; Work; Zinc Fingers; adaptive immunity; base; cytokine; genetic regulatory protein; human disease; in vivo; mRNA Stability; nucleic acid binding protein; overexpression; paralogous gene; protein expression; protein transport; response; transcription factor

DESCRIPTION (provided by applicant): T helper (TH) cells are the central organizers of adaptive immunity. TH cell function is specified by the effector cytokines they produce. Regulation of TH cell cytokine secretion is not well understood. Our recent data indicate that membrane-associated nucleic acid binding protein ([Mnab], also termed Roquin2, encoded by Rc3h2) is involved in control of TH cell effector function. Mnab shares with its paralog Roquin (encoded by Rc3h1) a highly conserved amino (N)- terminus that bears RING, ROQ and CCCH domains, whereas Mnab possesses a unique hydrophobic C-terminus. Roquin, an RNA-binding protein, interacts with Icos messenger RNA (mRNA) through its ROQ and CCCH-zinc finger domains, thereby regulating its stability and turnover. Sanroque mice, bearing a single point mutation (M199R) in the ROQ domain of Roquin, develop an autoimmune syndrome resembling systemic lupus erythematosus (SLE) in humans due to increased expression of ICOS on T cells and overrepresented follicular helper T (Tfh) cell compartment in the CD4+ T cells. Recently, Mnab was shown to play a redundant role with Roquin in Tfh cell development via repression of Icos and Ox40 mRNAs. Whether Mnab also targets other mRNAs and regulates function of other TH lineages is unclear. In our preliminary studies, we found that in vitro, Mnab deficiency in both RING and ROQ domains led to profound defects of effector cytokine production in TH1, TH2 and TH17 cells, suggesting an important role of its distinct hydrophobic C-terminus. The overall objective of this project is to determine the role of Mnab in TH cell effector function and the molecular basis. Our central hypothesis is that Mnab targets mRNAs encoding proteins in a common pathway that is critical in TH cell effector cytokine production. Our current data support that instead, Mnab stabilizes mRNAs in the stress pathway that is required for the secretory cells. In this proposal, we will first, determine the role of Mnab in TH cell differentiation and function in vitro and in vivo; second, determine the mRNA targets of Mnab in TH cells; third, determine the mechanism by which Mnab modulates mRNA stability. This study will reveal mechanistic information of TH cell effector function. Manipulation of the corresponding pathways may be of therapeutic benefit in human disease, such as autoimmune disorders.

描述（由申请人提供）：辅助性T细胞（TH）是适应性免疫的中心组织者。TH细胞的功能是由它们产生的效应细胞因子决定的。TH细胞细胞因子分泌的调控尚不清楚。我们最近的数据表明，膜相关核酸结合蛋白（[Mnab]，也称为Roquin2，由Rc3h2编码）参与控制TH细胞效应功能。Mnab与它的同源基因Roquin（由Rc3h1编码）共享一个高度保守的氨基(N)端，包含RING、ROQ和CCCH结构域，而Mnab具有一个独特的疏水c端。Roquin是一种RNA结合蛋白，通过其ROQ和ccch -锌指结构域与Icos信使RNA （mRNA）相互作用，从而调节其稳定性和周转。携带Roquin ROQ结构域单点突变（M199R）的Sanroque小鼠，由于T细胞上ICOS的表达增加和CD4+ T细胞中滤泡辅助性T （Tfh）细胞室的过度表达，发展出一种类似于人类系统性红斑狼疮（SLE）的自身免疫性综合征。最近，研究表明Mnab通过抑制Icos和Ox40 mrna在Tfh细胞发育中与Roquin一起发挥冗余作用。Mnab是否也靶向其他mrna并调节其他TH谱系的功能尚不清楚。在我们的初步研究中，我们发现在体外，Mnab在RING和ROQ结构域的缺乏导致TH1， TH2和TH17细胞中效应细胞因子产生的严重缺陷，这表明其独特的疏水c端发挥了重要作用。该项目的总体目标是确定Mnab在TH细胞效应功能中的作用