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 最佳的免疫调节对于分离抗原的肠道粘膜上皮至关重要。 来自身体无菌内核的丰富肠腔除了形成物理屏障外，上皮细胞 还执行重要的消化功能和由入侵病原体或过量引起的任何组织损伤 炎症会危及这一关键边界的完整性，粘膜免疫系统受到测试。 面临着独特的挑战，既要以最佳方式提供即时保护，又要以最少的成本做到这一点 这种困境对免疫细胞施加持续的压力来调整其免疫功能。 其功能与能够保护粘膜边界但不破坏它的防御作用相兼容。 这对于 CD4 T 辅助细胞 (Th) 来说尤其是一个问题，它们有可能分化为 Treg 和 抑制保护性免疫反应或炎症效应细胞，如可启动的 Th17 细胞 过度炎症并诱发严重的免疫病理最近，我们发现成熟的CD4 T。 迁移到肠上皮的细胞通过功能性转移来适应环境 抑制性或炎症性 Th 命运，而是重新编程成为保护性 CD8 样细胞毒性效应子 CD4 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。 粘膜环境和重编程过程中的缺陷导致高度 炎症性 Th17 T 细胞会导致肠道严重组织破坏，尽管极其重要， 对于驱动成熟细胞重编程过程的分子机制或因素一无所知。 然而，CD4 T 细胞的初步研究发现了一种新型长非编码 RNA (LncRNA)， 我们称之为 Switch，因为我们发现它在 CD4 CTL 前体细胞中独特表达，但是 更重要的是因为它的表达直接与依赖Runx3的CTL的开启相关 基因转录程序以及体外 RORγt 和 Foxp3 控制的 CD4 Th 命运的关闭 此外，我们发现 Switch 的功能丧失会损害 T 细胞。 CD4 Th 细胞重编程为 CTL，并导致高致病性 Th17 T 细胞在 这些观察结果支持 Switch 作为 CD4 可塑性的“主调节器”以及调节器的作用。 调节粘膜 CD4 T 细胞功能命运的机制的关键控制器 我们建议在此阐明肠道粘膜界面的独特挑战。 这种新型 LncRNA Switch 能够充当 CD4 T 中心枢纽的分子机制 细胞可塑性超越 Th 命运，并将成熟 CD4 T 细胞重新引导至 Runx3 控制的 CTL 谱系命运，同时抑制导致 CD4 T 细胞功能分化为的替代途径 炎症性 RORγt 控制的 Th17 细胞或抑制性 Foxp3 控制的 Treg 细胞。