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.

总结 最佳的免疫调节在分离抗原的肠粘膜上皮中是必不可少的- 从身体无菌的内部核心丰富的肠腔。除了形成物理屏障外， 也进行重要的消化功能和任何组织损伤，由入侵的病原体或过度诱导 炎症会危及这一关键边界的完整性。因此，粘膜免疫系统是 面临着独特的挑战，既要提供最佳和即时的保护， 对组织的损伤。这种困境给免疫细胞施加了持续的压力，以调整其免疫功能。 以与能够保护粘膜边界但不破坏它的防御作用相容的方式起作用。 这对于CD 4辅助性T（Th）细胞尤其是一个问题，其具有分化为Treg的潜力， 抑制保护性免疫反应或炎症效应细胞，如Th 17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CD 4 T细胞 迁移到肠上皮的细胞通过功能性地从它们的 而是重编程成为保护性CD 8样细胞毒性效应子 细胞CD 4细胞重编程为细胞毒性T淋巴细胞（CTL）是使其适应的关键过程 在重编程过程中的粘膜环境和缺陷导致产生高度 炎性Th 17 T细胞，导致肠道中严重的组织破坏。虽然非常重要， 目前还不清楚在成熟细胞中驱动重编程过程的分子机制或因素， CD 4 T细胞。然而，初步研究发现了一种新的长非编码RNA（LncRNA）， 我们称之为Switch，因为我们发现它只在CD 4 CTL前体细胞中表达， 更重要的是因为它的表达直接与Runx 3依赖性CTL的启动相关 基因转录程序和RORγt-和Foxp 3-控制的CD 4 Th命运的关闭 和体内活化的成熟CD 4 T细胞。此外，我们发现Switch功能的丧失损害了 CD 4 Th细胞重编程为CTL，并导致高致病性Th 17 T细胞在细胞中的积累。 肠子这些观察结果支持开关作为CD 4可塑性的“主调节器”以及CD 4可塑性的“主调节器”的作用。 调节粘膜CD 4 T细胞功能命运的机制的关键控制者， 与肠粘膜界面处的独特挑战相容。我们在此提议阐明 这种新的LncRNA，开关，能够作为CD 4 T细胞的中心枢纽的分子机制， 细胞可塑性，其延伸超出Th命运并将成熟的CD 4 T细胞重定向至Runx 3控制的CTL 同时抑制导致CD 4 T细胞功能性分化为 炎性RORγt控制的Th 17细胞或抑制性Foxp 3控制的Treg。