Ikaros regulates T helper cell fate decisions

Ikaros 调节 T 辅助细胞的命运决定

• 批准号: 8086019
• 负责人: Melissa A Brown
• 金额: $ 38.13万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-15 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8086019
• 关键词: Acute; Antigens; Bacteria; Biological Assay; CD4 Positive T Lymphocytes; Cell Line; Cell Lineage; Cells; Chromatin; Chromatin Remodeling Factor; Cytokine Gene; DNA Methylation; Deoxyribonuclease I; Development; Dominant-Negative Mutation; Ectopic Expression; Event; Gene Expression; Gene Targeting; Genes; Genetic Transcription; Helper-Inducer T-Lymphocyte; Hematopoietic; Histone Acetylation; Histone H3; Hypersensitivity; IL4 gene; Immune; Immunity; In Vitro; Interleukin-10; Interleukin-12; Interleukin-17; Interleukin-4; Interleukin-6; Laboratories; Lymphoid; Molecular; Molecular Conformation; Nucleic Acid Regulatory Sequences; Organ; Pathologic; Pathology; Pathway interactions; Peripheral; Phenotype; Play; Production; Protein Isoforms; Proteins; Regulatory T-Lymphocyte; Role; Sequence-Specific DNA Binding Protein; Signal Pathway; T-Lymphocyte; Th1 Cells; Th2 Cells; Time; Virus; base; cell type; cytokine; extracellular; fungus; histone modification; indexing; pathogen; response; transcription factor

When a na�ve CD4 T helper (Th) cell encounters its cognate antigen on an antigen presenting cell in the secondary lymphoid organs it is triggered to undergo differentiation along one of at least four alternative differentiation pathways that give rise to either Th1, Th2, Th17 or T regulatory cells. Th1, Th2 and Th17 cells are defined by their ability to express a subset of signature cytokines (e.g. IFN?, IL- 4 and IL-17 respectively) that "help" other immune cells respond appropriately. T regulatory (Treg) cells, characterized by the expression of Foxp3, act to suppress Th cell responses and limit pathology. The fate of a na�ve cell is determined in a large part by the cytokine microenvironment present during priming. Whereas IL-12 promotes Th1 differentiation, IL-4 promotes Th2 differentiation, TGF� and IL-6 promote Th17 cell development and TGF�, in the absence of IL-6, leads to T regulatory cells. Such alternative pathways of differentiation by a single cell must involve both the activation and silencing of cell lineage-specific genes. Ikaros, a sequence-specific DNA binding protein expressed uniquely in hematopoietic cells, is an excellent candidate for playing such a role in Th cell fate decisions. Ikaros can recruit both activating and suppressive chromatin remodeling complexes to particular gene loci. Best studied in the context of early T cell development in the thymus, several lines of evidence from our laboratories demonstrate that Ikaros also influences peripheral T cell gene expression. For example, in vitro Th2 differentiation, as defined by the production of the hallmark cytokines IL-4 and IL-10, cannot proceed efficiently in the absence of Ikaros. Indeed, na�ve Ikarosnull CD4 T cells default to an IFN3-producing Th1 phenotype under Th2- skewing conditions. In addition, the loss of ability to express IL-4 in Ikarosnull T cells corresponds with a histone H3 hypoacetylation within the type 2 cytokine locus. Finally, Ikaros directly associates with several type 2 cytokine locus regulatory regions in na�ve CD4 T cells. We propose it acts to either activate or suppress lineage-specific gene expression via recruitment of distinct chromatin remodeling complexes to specific Th cell loci or through effects on expression of lineage determining transcription factors such as GATA-3 (Th2) or Tbet (Th1). The specific aims are: 1) To determine whether Ikaros- dependent Th2 cytokine expression is due to its effects on Th2 lineage commitment and/or acute transcription; 2) To determine how Ikaros influences the acquisition of type 2 cytokine locus accessibility in Th2 cells; 3) To determine how Ikaros represses IFN3 expression in Th2 cells. An understanding of molecular events that regulate CD4 T cell fate decisions is important for devising better therapies aimed at promoting a protective and diverting a pathologic response.

当一个天真的人半活性CD 4辅助性T（Th）细胞在次级淋巴器官中的抗原呈递细胞上遇到其同源抗原，其被触发沿着至少四种替代性分化途径之沿着经历分化，所述分化途径产生Th 1、Th 2、Th 17或T调节细胞。Th 1、Th 2和Th 17细胞通过其表达特征细胞因子（例如IFN？，IL- 4和IL-17），“帮助”其他免疫细胞做出适当的反应。以Foxp 3的表达为特征的调节性T（Treg）细胞起到抑制Th细胞应答和限制病理的作用。幼稚细胞的命运在很大程度上由引发期间存在的细胞因子微环境决定。而IL-12促进Th 1分化，IL-4促进Th 2分化，TGF β 12和IL-6促进Th 17细胞发育，TGF β 12在缺乏IL-6的情况下导致T调节细胞。这种由单个细胞分化的替代途径必须涉及细胞谱系特异性基因的激活和沉默。Ikaros是一种在造血细胞中表达的序列特异性DNA结合蛋白，是Th细胞命运决定中发挥这种作用的极好候选者。Ikaros可以招募激活和抑制染色质重塑复合物到特定的基因位点。在胸腺中早期T细胞发育的背景下进行了最好的研究，来自我们实验室的几条证据表明，Ikaros也影响外周T细胞基因表达。例如，体外Th 2分化，如由标志性细胞因子IL-4和IL-10的产生所定义的，在不存在Ikaros的情况下不能有效地进行。事实上，在Th 2偏斜条件下，天然的Ikarosnull CD 4 T细胞默认为产生IFN 3的Th 1表型。此外，在Ikarosnull T细胞中表达IL-4的能力的丧失对应于2型细胞因子基因座内的组蛋白H3低乙酰化。最后，Ikaros直接与天然CD 4 T细胞中的几个2型细胞因子基因座调控区相关。我们提出，它的作用是通过招募不同的染色质重塑复合物到特定的Th细胞位点或通过影响谱系决定转录因子如加塔-3（Th 2）或Tbet（Th 1）的表达来激活或抑制谱系特异性基因表达。具体目标是：1）确定Ikaros依赖性Th 2细胞因子表达是否是由于其对Th 2谱系定型和/或急性转录的影响; 2）确定Ikaros如何影响Th 2细胞中2型细胞因子位点可及性的获得; 3）确定Ikaros如何抑制Th 2细胞中IFN 3的表达。了解调节CD 4 T细胞命运决定的分子事件对于设计旨在促进保护性和转移病理反应的更好疗法是重要的。