Agnihotri Parul, Robertson Nicholas M, Umetsu Sarah E, Arakcheeva Ksenia, Winandy Susan
Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, MA, USA.
Department of Microbiology-Immunology, Northwestern University, Chicago, IL, USA.
Immunology. 2017 Nov;152(3):494-506. doi: 10.1111/imm.12786. Epub 2017 Aug 23.
Ikaros is a transcription factor that regulates lymphocyte development from the level of the haematopoietic stem cell. Lack of Ikaros reduces the ability of progenitor cells to commit to the T-cell lineage, resulting in reduced numbers of early thymic T-cell progenitors and mature T cells. Mature CD4 T cells that lack Ikaros have defects in proliferation, T helper cell differentiation, cytokine expression and the ability to become anergic. A role for Ikaros in the naive T cell has not yet been identified. The receptors interleukin-7 receptor α (IL-7Rα) and l-selectin are important for ensuring survival and proper homing of naive T cells, respectively. Here we show that lack of Ikaros leads to reduced expression of these receptors in naive T cells, which impacts their ability to home and survive in response to IL-7. We define the mechanism underlying this phenotype as a requirement for Ikaros in maintenance of expression of Foxo1, a transcriptional regulator that is required for their expression. We also demonstrate that CD4 T cells lacking Ikaros are significantly crippled in their ability to become induced regulatory T cells, a phenotype also linked to reduced Foxo1 expression. Finally, we show that restoring Ikaros function to Ikaros-deficient CD4 T cells increases levels of Foxo1 message. Together, these studies define, for the first time, a role for Ikaros in naive T cells and establish it as the first transcriptional regulator required for maintaining levels of Foxo1 gene expression in these cells.
Ikaros是一种转录因子，它在造血干细胞水平上调节淋巴细胞的发育。缺乏Ikaros会降低祖细胞定向分化为T细胞谱系的能力，导致早期胸腺T细胞祖细胞和成熟T细胞数量减少。缺乏Ikaros的成熟CD4 T细胞在增殖、辅助性T细胞分化、细胞因子表达以及产生无反应性的能力方面存在缺陷。Ikaros在初始T细胞中的作用尚未明确。白细胞介素-7受体α（IL-7Rα）和L-选择素受体分别对确保初始T细胞的存活和正常归巢很重要。在此，我们表明缺乏Ikaros会导致初始T细胞中这些受体的表达减少，这影响了它们对IL-7做出反应而归巢和存活的能力。我们将这种表型的潜在机制定义为Ikaros对维持Foxo1表达的需求，Foxo1是一种转录调节因子，其表达需要Ikaros。我们还证明，缺乏Ikaros的CD4 T细胞在诱导生成调节性T细胞的能力上严重受损，这种表型也与Foxo1表达降低有关。最后，我们表明将Ikaros功能恢复到缺乏Ikaros的CD4 T细胞中会增加Foxo1信使核糖核酸的水平。总之，这些研究首次确定了Ikaros在初始T细胞中的作用，并将其确立为维持这些细胞中Foxo1基因表达水平所需的首个转录调节因子。
