Ikaros regulates T helper cell fate decisions

当na�ve CD4 T辅助细胞（Th）在次级淋巴器官的抗原呈递细胞上遇到其同源抗原时，它被触发沿着至少四种分化途径之一进行分化，产生Th1， Th2， Th17或T调节细胞。Th1、Th2和Th17细胞是由它们表达一组特征细胞因子(如IFN？（分别为IL- 4和IL-17），“帮助”其他免疫细胞做出适当反应。T调节性细胞（Treg）以Foxp3的表达为特征，可抑制T细胞反应并限制病理。na�ve细胞的命运在很大程度上取决于启动期间存在的细胞因子微环境。IL-12促进Th1分化，IL-4促进Th2分化，TGF�和IL-6促进Th17细胞发育，而TGF�在缺乏IL-6的情况下导致T调节性细胞。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独特表达的序列特异性DNA结合蛋白，是在细胞命运决定中发挥这种作用的极好候选者。Ikaros可以在特定的基因位点上招募激活和抑制染色质重塑复合物。在胸腺早期T细胞发育的背景下进行了最好的研究，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Th2分化，由标志性细胞因子IL-4和IL-10的产生所定义，在没有Ikaros的情况下不能有效地进行。事实上，na�的Ikarosnull CD4 T细胞默认ifn3产生Th1表型在Th2-偏斜条件下。此外，Ikarosnull T细胞中IL-4表达能力的丧失与2型细胞因子位点内的组蛋白H3低乙酰化相对应。最后，Ikaros直接与na�个CD4 T细胞中的几个2型细胞因子位点调控区域相关。我们认为它通过募集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GATA-3 （Th2）或Tbet （Th1）的表达来激活或抑制谱系特异性基因表达。具体目的是：1)确定Ikaros依赖性Th2细胞因子表达是否由于其对Th2谱系承诺和/或急性转录的影响；2)确定Ikaros如何影响Th2细胞2型细胞因子位点可及性的获得；3)确定Ikaros如何抑制Th2细胞中IFN3的表达。了解调节CD4 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治疗方法非常重要。

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.