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.

中枢神经系统自动免疫中的摘要THGM细胞 THGM细胞（THGM-CSF）是一个新描述的子集，其特征是GM-CSF的产生，但 缺乏既定细胞的签名细胞因子和主转录因子（TF）的表达 血统。在我们的分析中，THGM细胞比在血液中比Th2和Th17细胞更丰富 健康的受试者，甚至在MS患者中更是如此。尽管THGM单元具有某些独特的特征 需要进一步的研究来阐明这些疾病及其在健康和疾病中的作用。 thgm细胞 在自适应EAE模型中是高度脑型的，可以在小鼠的中枢神经系统中很容易找到它们 与直接的EAE。重要的是，THGM细胞富集在MS患者的脑脊液中，他们也 与健康个体相比，循环THGM细胞的数量更高。这些发现表明THGM 细胞有助于CNS自身免疫的发病机理，但该受试者只是最小的研究。超过 所有这些，我们的数据和发布的发现使我们假设THGM细胞起着重要的致病作用 在自身免疫性神经炎症中，MS和EAE。我们将在以下具体目的中检验这一假设： 目的1。确定THGM细胞的起源，并表征其GM-CSF之间的关系 表达和表型。人和小鼠THGM细胞都可以直接与 幼稚的CD4+ T细胞体外；但是，尚不清楚体内的Thgm细胞是来自幼稚的前体还是 转换其表型的谱系。我们假设体内Thgm细胞直接从幼稚 CD4+ T细胞。此外，我们将研究GM-CSF是THGM细胞表型还是 这些细胞具有独特的总体表型，与GM-CSF表达无关。 目的2。研究THGM细胞在自身免疫性神经炎症中的作用。最近的发现有 建议THGM细胞有助于CNS自身免疫性，因为MS患者的代表性过高 PBMC，它们通过被动转移影响小鼠的EAE。这导致我们假设THGM细胞播放 在MS和EAE中具有重要的致病作用。在小鼠中，我们将表征CNS自身免疫性 THGM细胞，而在人类系统中，我们将测试其在有机脑切片中的致病性，而 表征MS脑病变中的THGM细胞。 目标3。确定候选TF在塑造THGM表型中的作用。 THGM细胞不表达 已建立的谱系的主TF，表明THGM表型是由TF差异化的 在THGM细胞中表达。我们的发现构成了THGM表型的假设的基础 与其他TH细胞相比，通过THGM细胞自然过表达的一组TF。我们将检验这个假设 使用缺乏候选TF的小鼠，并通过击倒人CD4+ T细胞中候选TF的表达。 从这些研究中获得的知识可能会改变CNS自身免疫的当前概念。