Transcriptional regulation of IL-15 expression during hematopoiesis.
Transcriptional regulation of IL-15 expression during hematopoiesis.
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DOI：
10.4049/jimmunol.1301389
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发表时间：
2013-09-15
期刊：
影响因子：
--
通讯作者：
Lefrançois L
中科院分区：
文献类型：
--
作者：
Colpitts SL;Stonier SW;Stoklasek TA;Root SH;Aguila HL;Schluns KS;Lefrançois L
树突状细胞（dc）是细胞因子白介素-15 （IL-15）最常被研究的来源。使用IL-15报告基因转基因小鼠，我们最近发现了传统dc亚群（CD8+和CD8-）表达IL-15水平的差异。在这里，我们发现IL-15启动子活性在造血来源细胞亚群中受到差异调节，IL-15的表达主要局限于髓系。相比之下，淋巴系的成熟细胞表达很少或没有IL-15活性。令人惊讶的是，我们发现造血干细胞（Lin-Sca-1+c-kit+; lsk）表达高水平的IL-15，这表明IL-15的表达在淋巴细胞发育过程中被消灭了。在T细胞的情况下，这种下调是notch依赖性的，并以逐步成熟的模式发生，与T细胞命运的增加和承诺一致。最后，我们进一步证明IL-15的表达在DC发育过程中也受到控制，IL-15产生的关键调控活性发生在DC前分支点，导致IL-15+ CD8+和IL-15-/低CD8-DC亚群的产生。因此，IL-15的表达与骨髓免疫细胞和淋巴免疫细胞的细胞命运相协调。
Dendritic cells (DCs) are the most commonly studied source of the cytokine interleukin-15 (IL-15). Using an IL-15 reporter transgenic mouse, we have recently shown previously unappreciated differences in the levels of IL-15 expressed by subsets of conventional DCs (CD8+ and CD8-). Here we show that IL-15 promoter activity was differentially regulated in subsets of hematopoietically derived cells with IL-15 expression largely limited to myeloid lineages. In contrast, mature cells of the lymphoid lineages expressed little to no IL-15 activity. Surprisingly, we discovered that hematopoietic stem cells (Lin-Sca-1+c-kit+; LSKs) expressed high levels of IL-15 suggesting that IL-15 expression was extinguished during lymphoid development. In the case of T cells, this downregulation was Notch-dependent and occurred in a step-wise pattern coincident with increasing maturation and commitment to a T cell fate. Finally, we further demonstrate that IL-15 expression was also controlled throughout DC development, with key regulatory activity of IL-15 production occurring at the pre-DC branch point leading to the generation of both IL-15+ CD8+ and IL-15-/low CD8-DC subsets. Thus, IL-15 expression is coordinated with cellular fate in myeloid versus lymphoid immune cells.
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