ThGM Cells in CNS Autoimmunity

ThGM细胞在CNS自身免疫中的作用 ThGM细胞（ThGM-CSF）是新近描述的以产生GM-CSF为特征的Th亚群，但 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细胞明显比Th 2和Th 17细胞更丰富， 健康受试者，在MS患者中更是如此。虽然ThGM细胞具有一些独特的特征， 然而，由于这两种基因的不同，需要进一步研究来澄清这一区别，以及它们在健康和疾病中的作用。ThGM细胞 在过继性EAE模型中具有高度致脑炎性，并且它们可以容易地在小鼠的CNS中发现 直接EAE。重要的是，ThGM细胞在MS患者的脑脊液中富集， ThGM细胞的数量比健康人多。这些发现表明， 细胞参与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假设ThGM细胞起着重要的致病作用， 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： 目标1.确定ThGM细胞的来源，并表征它们与GM-CSF之间的关系。 表达和表型。人和小鼠ThGM细胞都可以容易地直接从 体外的幼稚CD 4 + T细胞;然而，目前还不清楚体内的ThGM细胞是否来源于幼稚前体细胞，或者 改变了其表型的Th谱系。我们假设ThGM细胞在体内直接从幼稚的 CD 4 + 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 这些细胞具有独特的总体表型，与GM-CSF表达无关。 目标二。探讨ThGM细胞在自身免疫性神经炎症中的作用。最近的调查结果表明， 提示ThGM细胞有助于CNS自身免疫，因为它们在MS患者中过度表达。 PBMC，并且它们通过被动转移在小鼠中诱导EAE。这让我们假设ThGM细胞发挥着 在MS和EAE中具有重要的致病作用。在小鼠中，我们将描述由以下物质诱导的中枢神经系统自身免疫性 ThGM细胞，而在人类系统中，我们将在器官型脑切片中测试其致病性， 表征MS脑病变中的ThGM细胞。 目标3：确定候选TF在形成ThGM表型中的作用。ThGM细胞不表达 已建立Th谱系的主TF，表明ThGM表型由TF（s）不同地形成 在ThGM细胞中表达。我们的研究结果为ThGM表型是直接的假设奠定了基础。 与其他Th细胞相比，ThGM细胞中天然过表达的一组TF。我们将检验这一假设 使用缺乏候选TF的小鼠并通过敲低候选TF在人CD 4 + T细胞中的表达。 从这些研究中获得的知识可能会修改目前的CNS自身免疫的概念。

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.