Control of the Functional Fate of CD4 T Cells by LncRNA-Switch

LncRNA-Switch 对 CD4 T 细胞功能命运的控制

• 批准号: 9170246
• 负责人: HILDE MC CHEROUTRE
• 金额: $ 53.55万
• 依托单位: LA JOLLA INSTITUTE FOR IMMUNOLOGY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9170246
• 关键词: Abbreviations; Antigens; CD4 Positive T Lymphocytes; CD8B1 gene; Cells; Chromatin; Colitis; Cytotoxic T-Lymphocytes; DNA; Defect; Effector Cell; Enhancers; Enterocytes; Environment; Epigenetic Process; Epithelial; Epithelial Cells; Epithelium; Equilibrium; GATA3 gene; Gene Expression; Gene Targeting; Generations; Genetic Transcription; Genome; Helper-Inducer T-Lymphocyte; Immune; Immune response; Immune system; Immunity; In Vitro; Inflammation; Inflammatory; Intestines; Invaded; Killer Cells; Lead; MHC Class II Genes; Maps; Mediating; Modeling; Molecular; Names; Pathology; Pathway interactions; Phenotype; Play; Population; Process; Regulation; Regulatory T-Lymphocyte; Repression; Research Design; Role; Seminal; Site; Sterility; Stretching; System; T-Lymphocyte; Technology; Testing; Thymus Gland; Time; Tissues; Untranslated RNA; base; cytotoxic; design; epigenomics; functional plasticity; genome-wide; immune function; in vivo; intestinal epithelium; loss of function; novel; pathogen; precursor cell; pressure; programs; promoter; thymocyte; transcription factor; transcriptomics

SUMMARY Optimal immune regulation is essential at the mucosal epithelium of the intestine that separates the antigen- rich gut lumen from the sterile inner core of the body. In addition to forming a physical barrier, the epithelium also carries out vital digestive functions and any tissue damage, induced by invading pathogens or excessive inflammation can jeopardize the integrity of this critical border. Consequently, the mucosal immune system is faced with the unique challenge to provide optimal and immediate protection but also to do so with the least damage to the tissue. This dilemma imposes a constant pressure for the immune cells to adjust their immune function in a way that is compatible with a defensive role able to protect the mucosal border but not destroy it. This is especially an issue for CD4 T helper (Th) cells, which have the potential to differentiate to Treg and suppress protective immune responses or to inflammatory effector cells like the Th17 cells that can initiate excessive inflammation and induce severe immune pathology. Recently, we discovered that mature CD4 T cells that migrate to the intestinal epithelium adapt to the environment by functionally divert from their suppressive or inflammatory Th fate but instead reprogram to become protective CD8-like cytotoxic effector cells. The reprogramming of CD4 cells to cytotoxic T lymphocytes (CTL) is a critical process that adapts them to the mucosal environment and defects in the reprogramming process lead to the generation of highly inflammatory Th17 T cells that cause severe tissue destruction in the intestine. Although extremely important, nothing is known about the molecular mechanism or factors that drive the reprogramming process in mature CD4 T cells. Preliminary studies however lead to the discovery of a novel long non-coding RNA(LncRNA), which we have called, Switch, because we found that it is uniquely expressed in CD4 CTL precursor cells but more importantly because its expression directly associates with the switching-on of the Runx3-dependent CTL gene transcription program and the switching-off of the RORγt- and Foxp3-controlled CD4 Th fates in in vitro- and in vivo-activated mature CD4 T cells. In addition, we found that loss-of-function of Switch impaired the reprogramming of CD4 Th cells to CTL and led to the accumulation of highly pathogenic Th17 T cells in the intestine. These observations support a role for Switch as a “master regulator” of CD4 plasticity as well as a critical controller of the mechanism to adapt the functional fate of mucosal CD4 T cells in a way that is compatible with the unique challenges at the mucosal interface of the intestine. We propose here to elucidate the molecular mechanisms by which this novel LncRNA, Switch, is able to function as a central hub for CD4 T cell plasticity that stretches beyond the Th fates and re-directs mature CD4 T cells to the Runx3-controlled CTL lineage fate while suppressing the alternative pathways that lead to functional differentiation of CD4 T cells into inflammatory RORγt controlled Th17 cells or suppressive Foxp3-controlled Treg.

概括 最佳免疫调节在肠的粘膜上皮至关重要，将抗原分离 来自人体无菌内核的丰富肠腔。除了形成物理屏障外，上皮 还可以执行重要的消化功能和任何组织损伤，这是由入侵的病原体或多余的 炎症会危害这个关键边界的完整性。因此，粘膜免疫系统是 面对独特的挑战，以提供最佳和直接的保护，但也至少要这样做 损坏组织。这种困境不可能使免疫细胞调节其免疫力的恒定压力 功能与能够保护粘膜边界但不能破坏粘膜边界的防御作用兼容的方式。 对于CD4 T辅助器（Th）细胞而言，这尤其是一个问题，该细胞有可能区分Treg和 抑制受保护的免疫反应或炎症效应细胞（如Th17细胞） 过度炎症并诱导严重的免疫病理学。最近，我们发现成熟的CD4 T 迁移到肠上皮的细胞通过功能从其功能转移而适应环境 抑制性或炎症性的命运，但重新编程以受保护的CD8样细胞毒性效应器 细胞。将CD4细胞重编程为细胞毒性T淋巴细胞（CTL）是适应它们的关键过程 到粘膜环境和重编程过程中的缺陷导致高度产生 炎症Th17 T细胞，导致肠道严重的组织破坏。尽管非常重要，但是 关于驱动重编程过程的分子机制或因素，对成熟过程一无所知 CD4 T细胞。然而，初步研究导致发现了新型长的非编码RNA（LNCRNA）， 我们称之为切换，因为我们发现它在CD4 CTL前体细胞中唯一表达，但是 更重要的是，因为它的表达直接与runx3依赖性CTL的开关联系在一起 基因转录程序以及RORγT和FOXP3控制的CD4 TH命运的关闭 和体内活化的成熟CD4 T细胞。此外，我们发现开关的功能丧失受损 将CD4细胞重新编程为CTL，并导致高度致病性Th17 T细胞的积累 肠。这些观察结果支持开关作为CD4可塑性的“主调节器”以及 该机制的关键控制器以一种方式适应粘膜CD4 T细胞的功能命运的方式 与肠粘膜界面所面临的独特挑战兼容。我们在这里提议阐明 这种新颖的lncRNA开关能够充当CD4 T的中心枢纽的分子机制 细胞可塑性超出了命运，并将成熟的CD4 T细胞重新引导到Runx3控制的CTL 血统命运在抑制导致CD4 T细胞功能分化的替代途径中 炎症性RORγT控制TH17细胞或抑制FOXP3控制的Treg。