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.

中枢神经系统自身免疫中的 ThGM 细胞总结 ThGM 细胞 (ThGM-CSF) 是新描述的 Th 亚群，其特征是产生 GM-CSF，但是 缺乏已建立的 Th 细胞的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，ThGM 细胞在血液中明显多于 Th2 和 Th17 细胞。 健康受试者，多发性硬化症患者更是如此。尽管 ThGM 细胞具有一些独特的特征 谱系，需要进一步研究来澄清这种区别，以及它们在健康和疾病中的作用。 ThGM细胞 在过继性 EAE 模型中具有高度致脑炎性，并且很容易在小鼠的中枢神经系统中发现它们 直接EAE。重要的是，多发性硬化症患者的脑脊液中富含 ThGM 细胞，这些患者也 与健康个体相比，具有更多数量的循环 ThGM 细胞。这些发现表明 ThGM 细胞有助于中枢神经系统自身免疫的发病机制，但这一主题的研究很少。超过 总之，我们的数据和已发表的研究结果使我们推测 ThGM 细胞发挥着重要的致病作用 自身免疫性神经炎症、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 细胞的起源，并表征其 GM-CSF 之间的关系 表达和表型。人类和小鼠 ThGM 细胞都可以很容易地直接从 体外幼稚 CD4+ T 细胞；然而，尚不清楚体内的 ThGM 细胞是否源自幼稚前体，或者是 改变其表型的谱系。我们假设 ThGM 细胞在体内直接从幼稚细胞发育而来 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 无论 GM-CSF 表达如何，这些细胞都具有独特的整体表型。 目的2.研究ThGM细胞在自身免疫性神经炎症中的作用。最近的研究结果有 表明 ThGM 细胞有助于中枢神经系统自身免疫，因为它们在多发性硬化症患者中的比例过高 PBMCs，它们通过被动转移诱导小鼠 EAE。这使我们推测 ThGM 细胞发挥作用 在 MS 和 EAE 中具有重要的致病作用。在小鼠中，我们将表征由以下因素引起的中枢神经系统自身免疫： ThGM 细胞，而在人体系统中，我们将在器官型脑切片中测试其致病性，并且 表征多发性硬化症脑损伤中的 ThGM 细胞。 目标 3. 确定候选转录因子在塑造 ThGM 表型中的作用。 ThGM 细胞不表达 已建立的 Th 谱系的主要 TF，表明 ThGM 表型是由 TF 差异塑造的 在 ThGM 细胞中表达。我们的研究结果构成了 ThGM 表型是定向的假设的基础 与其他 Th 细胞相比，ThGM 细胞中自然过度表达的一组 TF。我们将检验这个假设 使用缺乏候选转录因子的小鼠并敲低人类 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当前中枢神经系统自身免疫的概念。