Ikaros enforces the costimulatory requirement for IL2 gene expression and is required for anergy induction in CD4+ T lymphocytes
Ikaros enforces the costimulatory requirement for IL2 gene expression and is required for anergy induction in CD4+ T lymphocytes
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DOI：
10.4049/jimmunol.179.11.7305
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发表时间：
2007-12-01
影响因子：
4.4
通讯作者：
Wells, Andrew D.
中科院分区：
文献类型：
--
作者：
Thomas, Rajan M.;Chunder, Neelanjana;Wells, Andrew D.
T细胞活化导致IL 2启动子处染色质的动态重塑和IL 2基因转录的诱导。这些过程都依赖于CD 28共刺激，但这种要求的分子基础尚不清楚。IL 2启动子包含Ikaros的共识结合元件，Ikaros是一种淋巴细胞特异性锌指DNA结合蛋白，可以通过募集染色质重塑复合物来调节基因表达。我们发现，在CD 4（+）T细胞中的天然Ikaros表现出序列特异性结合这些元件在体外，并与内源性IL 2启动子在体内相互作用，在某种程度上依赖于其DNA结合域。这种结合对IL 2基因的调节具有重要的影响，因为具有降低的Ikaros DNA结合活性的CD 4（+）T细胞不再需要来自TCR或CD 28的信号来在内源性IL 2启动子处进行组蛋白乙酰化，并且不再需要CD 28共刺激来表达IL 2基因。此外，具有降低的Ikaros活性的CD 4（+）T细胞对在不存在CD 28或IL-2 R信号的情况下由TCR连接诱导的克隆性无反应性具有抗性。这些结果确立了Ikaros作为IL 2基因的转录抑制因子，其通过调节染色质结构发挥作用，并且在诱导无反应性中具有专性作用。
T cell activation results in dynamic remodeling of the chromatin at the IL2 promoter and induction of IL2 gene transcription. These processes are each dependent upon CD28 costimulation, but the molecular basis for this requirement is not clear. The IL2 promoter contains consensus-binding elements for Ikaros, a lymphocyte-specific zinc-finger DNA-binding protein that can regulate gene expression by recruiting chromatin-remodeling complexes. We find that native Ikaros in CD4(+) T cells exhibits sequence-specific binding to these elements in vitro, and interacts with the endogenous IL2 promoter in vivo, in a manner dependent upon its DNA-binding domain. This binding has important consequences on the regulation of the IL2 gene, because CD4(+) T cells with reduced Ikaros DNA-binding activity no longer require signals from the TCR or CD28 for histone acetylation at the endogenous IL2 promoter, and no longer require CD28 costimulation for expression of the IL2 gene. Furthermore, CD4(+) T cells with reduced Ikaros activity are resistant to clonal anergy induced by TCR ligation in the absence of either CD28 or IL-2R signals. These results establish Ikaros as a transcriptional repressor of the IL2 gene that functions through modulation of chromatin structure and has an obligate role in the induction of anergy.