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 细胞的功能由它们产生的效应细胞因子决定。 TH 细胞细胞因子分泌的调节尚不清楚。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 TH 细胞效应功能的控制。 Mnab 与其旁系同源物 Roquin（由 Rc3h1 编码）共享一个高度保守的氨基 (N) 末端，带有 RING、ROQ 和 CCCH 结构域，而 Mnab 拥有独特的疏水性 C 末端。 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更新。 Sanroque 小鼠在 Roquin 的 ROQ 结构域中携带单点突变 (M199R)，由于 T 细胞上 ICOS 表达增加和滤泡辅助 T (Tfh) 细胞区室过多，因此会出现类似于人类系统性红斑狼疮 (SLE) 的自身免疫综合征在 CD4+ T 细胞中。最近，Mnab 被证明通过抑制 Icos 和 Ox40 mRNA 在 Tfh 细胞发育中与 Roquin 一起发挥冗余作用。 Mnab 是否还靶向其他 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，RING 和 ROQ 结构域中的 Mnab 缺陷导致 TH1、TH2 和 TH17 细胞中效应细胞因子产生的严重缺陷，表明其独特的疏水性 C 末端的重要作用。该项目的总体目标是确定 Mnab 在 TH 细胞效应功能中的作用和 分子基础。我们的中心假设是 Mnab 以共同途径靶向编码蛋白质的 mRNA，该途径对于 TH 细胞效应细胞因子的产生至关重要。我们目前的数据支持，Mnab 可以稳定分泌细胞所需的应激途径中的 mRNA。在本提案中，我们首先确定Mnab在体内外TH细胞分化和功能中的作用；其次，确定TH细胞中Mnab的mRNA靶点；第三，确定 Mnab 调节 mRNA 稳定性的机制。 本研究将揭示TH细胞效应功能的机制信息。操纵相应的途径可能对人类疾病（例如自身免疫性疾病）有治疗作用。