ThGM Cells in CNS Autoimmunity

中枢神经系统自身免疫中的 ThGM 细胞

• 批准号: 10299105
• 负责人: A.M. Rostami
• 金额: $ 39万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-12 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10299105
• 关键词: Address; Autoimmune; Autoimmune Diseases; Autoimmunity; Biology; Blood; Brain; CCL20 gene; CD4 Positive T Lymphocytes; CNS autoimmunity; Cell Lineage; Cell Shape; Cells; Cellular biology; Cerebrospinal Fluid; Classification; Complex; Data; Development; Disease; Experimental Autoimmune Encephalomyelitis; Future; Gene Expression Profile; Health; Human; Immune; Immunity; In Vitro; Individual; Inflammation; Interleukin-2; Knockout Mice; Knowledge; Lead; Lesion; Mediator of activation protein; Membrane; Modeling; Multiple Sclerosis; Multiple Sclerosis Lesions; Mus; Myeloid Cells; Names; Nature; Pathogenesis; Pathogenicity; Peripheral Blood Mononuclear Cell; Phenotype; Physiological; Play; Population; Process; Production; Proteome; Publishing; Role; Shapes; Slice; System; T-Lymphocyte; TNF gene; TNFSF6 gene; Testing; Time; cytokine; differential expression; immune system function; in vivo; knock-down; multiple sclerosis patient; neuroinflammation; novel therapeutic intervention; novel therapeutics; overexpression; single-cell RNA sequencing; transcription factor; transcriptome

SUMMARY ThGM Cells in CNS Autoimmunity ThGM cells (ThGM-CSF) are a newly described Th subset characterized by production of GM-CSF, but lacking expression of signature cytokines and master transcription factors (TF) for established Th cell lineages. In our analysis, ThGM cells were notably more abundant than Th2 and Th17 cells in the blood of healthy subjects, and even more so in MS patients. Although ThGM cells have some features of a distinct lineage, further study is needed to clarify that distinction, as well as their roles in health and disease. ThGM cells were highly encephalitogenic in the adoptive EAE model, and they can be readily found in the CNS of mice with direct EAE. Importantly, ThGM cells were enriched in the cerebrospinal fluid of MS patients, who also have greater numbers of circulating ThGM cells than healthy individuals. These findings suggest that ThGM cells contribute to the pathogenesis of CNS autoimmunity, but this subject has been only minimally studied. Over all, our data and published findings led us to hypothesize that ThGM cells play a significant pathogenic role in autoimmune neuroinflammation, MS and EAE. We will test this hypothesis in the following specific aims: Aim 1. To determine the origin of ThGM cells, and characterize the relationship between their GM-CSF expression and phenotype. Both human and mouse ThGM cells can be readily differentiated directly from naïve CD4+ T cells in vitro; however, it is unclear if ThGM cells in vivo originate from naïve precursors, or a Th lineage that switched its phenotype. We hypothesize that ThGM cells in vivo develop directly from naïve CD4+ T cells. In addition, we will study whether GM-CSF is a key determinant of ThGM cell phenotype, or these cells have a unique overall phenotype irrespective of GM-CSF expression. Aim 2. To study the role of ThGM cells in autoimmune neuroinflammation. Recent findings have suggested that ThGM cells contribute to CNS autoimmunity, as they are overrepresented in MS patients’ PBMCs, and they induce EAE in mice by passive transfer. This led us to hypothesize that ThGM cells play a significant pathogenic role in MS and EAE. In mice, we will characterize CNS autoimmunity induced by ThGM cells, while in the human system we will test their pathogenicity in organotypic brain slices, and characterize ThGM cells in MS brain lesions. Aim 3. To determine the role of candidate TFs in shaping ThGM phenotype. ThGM cells do not express master TFs of established Th lineages, suggesting that the ThGM phenotype is shaped by TF(s) differentially expressed in ThGM cells. Our findings form the basis for the hypothesis that the ThGM phenotype is directed by a set of TFs naturally overexpressed in ThGM cells compared to other Th cells. We will test this hypothesis using mice lacking candidate TFs and by knocking down expression of candidate TFs in human CD4+ T cells. Knowledge gained from these studies may modify the current concept of CNS autoimmunity.

ThGM细胞在中枢神经系统自身免疫中的研究进展 ThGM细胞(ThGM-CSF)是一种新发现的以产生GM-CSF为特征的Th亚群，但 已建立的Th细胞缺乏标志性细胞因子和主转录因子(TF)的表达 血统。在我们的分析中，在中国人的血液中，ThGM细胞明显比Th2和Th17细胞丰富。 健康受试者，在多发性硬化症患者中更是如此。尽管ThGM细胞具有一些明显的 关于血统，需要进一步研究以澄清这一区别，以及它们在健康和疾病中的作用。ThGM细胞 在过继的EAE模型中具有高度的脑源性，在小鼠的中枢神经系统中很容易发现它们 通过直接的EAE。重要的是，多发性硬化症患者的脑脊液中有丰富的ThGM细胞，他们也 比健康的人有更多数量的循环ThGM细胞。这些发现表明，ThGM 细胞参与了中枢神经系统自身免疫的发病机制，但这方面的研究还很少。完毕 总之，我们的数据和发表的研究结果让我们假设ThGM细胞起着重要的致病作用 在自身免疫性神经炎中，MS和EAE。我们将在以下具体目标中检验这一假设： 目的1.确定ThGM细胞的来源，并探讨其与GM-CSF的关系 表达和表型。人和小鼠的ThGM细胞都可以直接从 体外幼稚的CD4+T细胞；然而，目前尚不清楚体内的ThGM细胞是否起源于幼稚的前体细胞，或 这一血统改变了它的表型。我们假设体内的ThGM细胞直接从幼稚发育而来 CD4+T细胞。此外，我们将研究GM-CSF是否是ThGM细胞表型的关键决定因素，或者 这些细胞具有独特的整体表型，与GM-CSF的表达无关。 目的2.研究ThGM细胞在自身免疫性神经炎中的作用。最近的研究结果表明 提示ThGM细胞参与了CNS自身免疫，因为它们在MS患者中过度表达 PBMCs，并通过被动转移诱导小鼠EAE。这导致我们假设ThGM细胞在 在MS和EAE中起重要致病作用。在小鼠中，我们将表征由 ThGM细胞，而在人类系统中，我们将在器官型脑片中测试它们的致病性，以及 多发性硬化症脑部病变的ThGM细胞特征。 目的3.确定候选转铁蛋白在ThGM表型形成中的作用。ThGM细胞不表达 掌握已建立的Th谱系的Tf，提示ThGM表型是由Tf(S)不同地塑造的 在ThGM细胞中表达。我们的发现构成了ThGM表型被导向的假设的基础 与其他Th细胞相比，ThGM细胞中的一组转录因子自然过表达。我们将检验这一假设 使用缺乏候选转录因子的小鼠，并通过下调人类CD4+T细胞中候选转录因子的表达。 从这些研究中获得的知识可能会改变目前中枢神经系统自身免疫的概念。