Post-transcriptional Regulation of IL-21 in Human T Cells

人类 T 细胞中 IL-21 的转录后调控

• 批准号: 10404915
• 负责人: Deepak Angara Rao
• 金额: $ 8.95万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-15 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10404915
• 关键词: Affect; American; Antibodies; Antisense Oligonucleotides; Autoantibodies; Autoimmune Diabetes; Autoimmune Diseases; Autoimmune Hepatitis; B cell differentiation; B-Lymphocytes; BLR1 gene; Binding; Blood Circulation; CD4 Positive T Lymphocytes; CXCL13 gene; Celiac Disease; Cell Communication; Cell Differentiation process; Cell Fractionation; Cell Nucleus; Cell physiology; Cells; Chemotactic Factors; Clustered Regularly Interspaced Short Palindromic Repeats; Coculture Techniques; Cytometry; Cytoplasm; Enzymes; Funding; Generations; Genetic Transcription; Helper-Inducer T-Lymphocyte; Hour; Human; In Situ Hybridization; In Vitro; Interleukin-12; Joints; Kinetics; Laboratories; Length; Lymphoid Follicle; Mediating; Methods; Molecular; Mus; Pathologic; Patients; Pattern; Peripheral; Phenotype; Plasmablast; Plasmids; Population; Post-Transcriptional Regulation; Process; Production; RNA; Receptor Activation; Regulation; Research Personnel; Role; Signal Transduction; Small Interfering RNA; Small RNA; Source; Systemic Lupus Erythematosus; Systemic Scleroderma; T-Cell Receptor; T-Lymphocyte; Testing; Therapeutic; Time; Tissues; Transcript; Transcriptional Regulation; Transfection; Transforming Growth Factor beta; Untranslated RNA; Work; antigen-specific T cells; burden of illness; cell motility; cytokine; experimental study; in vivo; inhibitor; insight; interleukin-21; knock-down; mRNA Expression; memory CD4 T lymphocyte; novel; overexpression; response; secondary lymphoid organ; seropositive; therapeutic target; transcription factor; transcriptome sequencing

Project Summary/Abstract: Autoimmune diseases affect over 23 million Americans and impose a huge burden of disease. Many autoimmune diseases are characterized by pathologic T cell-B cell interactions and production of autoantibodies. The T cell populations that help B cells in autoimmune diseases vary in phenotype and include T follicular helper (Tfh) cells, which reside in follicles of secondary lymphoid organs, as well as T peripheral helper (Tph) cells, which are B cell-helper T cells that migrate to inflamed peripheral tissues such as the rheumatoid joint. Both Tfh cells and Tph cells make the cytokine IL-21, a cytokine essential for B cell differentiation into plasmablasts. In addition, both Tfh cells and Tph cells make CXCL13, a potent B cell chemoattractant. While Tph and Tfh cells can make both IL-21 and CXCL13, these two factors show marked differences in regulation: they are induced by different polarizing cytokines, regulated by different transcription factors, and enacted with different kinetics, such that T cells appear to rarely make both factors simultaneously. We hypothesize that the discordant expression of IL-21 and CXCL13 in controlled by a long noncoding RNA IL21AS1, which is highly expressed in T cells that make abundant CXCL13. In this project, we evaluate the hypothesis that IL21AS1 functions as an endogenous siRNA that inhibits IL-21 expression as T cells transition from initial IL-21 production to later CXCL13 production. We will test the effect of IL21AS1 on IL-21 expression in primary human T cells using knockdown and overexpression experiments. We will evaluate the cellular localization of IL21AS1 and its potential processing into endogenous siRNA. We will interrogate how the expression of IL21AS1 changes under conditions that induce either IL-21 or CXCL13 production by T cells. We expect that this project will reveal a novel mechanism regulating the expression of IL-21 in human T cells and the temporal switch in effector functions in these cells. Understanding the molecular control of these key T cell functions may allow new strategies to interfere with Tph and Tfh cell function therapeutically.

项目概要/摘要： 自身免疫性疾病影响超过2300万美国人，并造成巨大的疾病负担。许多 自身免疫性疾病的特征在于病理性T细胞-B细胞相互作用和 自身抗体在自身免疫性疾病中帮助B细胞的T细胞群在表型上不同，包括 T滤泡辅助细胞（Tfh），位于次级淋巴器官的滤泡中，以及T外周淋巴细胞 辅助性（Tph）细胞，其是迁移到发炎的外周组织（例如，淋巴细胞）的B细胞辅助性T细胞。 类风湿关节炎Tfh细胞和Tph细胞都产生细胞因子IL-21，这是B细胞必需的细胞因子 分化成浆母细胞。此外，Tfh细胞和Tph细胞都产生CXCL 13，一种有效的B细胞 化学引诱物虽然Tph和Tfh细胞可以产生IL-21和CXCL 13，但这两种因子显示出显著的 调节差异：它们由不同的极化细胞因子诱导，由不同的转录调节 因子，并以不同的动力学产生，使得T细胞似乎很少同时产生两种因子。 我们假设IL-21和CXCL 13的不一致表达是由一个长的非编码RNA控制的， IL 21 AS 1，其在产生丰富CXCL 13的T细胞中高度表达。在这个项目中，我们评估了 IL-21 AS 1作为内源性siRNA发挥功能，在T细胞转化时抑制IL-21表达的假设 从最初的IL-21产生到后来的CXCL 13产生。我们将测试IL-21 AS 1对IL-21表达的影响。 在原代人T细胞中使用敲低和过表达实验。我们将评估细胞 IL 21 AS 1的定位及其加工成内源性siRNA的潜力。我们将审问 在诱导T细胞产生IL-21或CXCL 13的条件下，IL 21 AS 1的表达发生变化。我们 预期该项目将揭示调节人T细胞中IL-21表达的新机制， 这些细胞中效应器功能的时间转换。了解这些关键T细胞的分子控制 功能可能允许新的策略来治疗性地干扰Tph和Tfh细胞功能。