High levels of IL-7 cause dysregulation of thymocyte development
High levels of IL-7 cause dysregulation of thymocyte development
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DOI：
10.1093/intimm/dxs067
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发表时间：
2012-10-01
影响因子：
4.4
通讯作者：
Gress, Ronald E.
中科院分区：
文献类型：
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作者：
El-Kassar, Nahed;Flomerfelt, Francis A.;Gress, Ronald E.
IL-7信号传导是胸腺细胞发育所必需的，其损失对胸腺功能具有严重的有害影响。胸腺细胞基质细胞相互作用和其他机制密切调节IL-7的表达。我们发现，通过过度表达IL-7来破坏这种调节会抑制T细胞的发育，并促进胸腺中广泛的B细胞淋巴细胞生成。我们的数据显示，高水平的IL-7否定了IL-7转基因小鼠和与OP 9-DL 1细胞共培养的胸腺细胞中Notch-1的功能。虽然胸腺细胞上存在高水平的IL-7 R，但细胞因子信号传导抑制因子-1表达的增加使IL-7下游信号传导变钝，导致PI 3 K-Akt途径中蛋白质的低磷酸化。因此，GSK 3保持活性并抑制Notch-1信号传导，如通过胸腺祖细胞中Hes-1和Deltex表达降低所观察到的。这是第一次证明高水平的IL-7拮抗Notch-1信号传导，并表明IL-7可能影响胸腺中T-与B-谱系的选择。
IL-7 signaling is required for thymocyte development and its loss has a severe deleterious effect on thymus function. Thymocytestromal cell interactions and other mechanisms tightly regulate IL-7 expression. We show that disruption of that regulation by over-expression of IL-7 inhibits T-cell development and promotes extensive B-cell lymphopoiesis in the thymus. Our data reveal that high levels of IL-7 negate Notch-1 function in thymocytes found in IL-7 transgenic mice and in co-culture with OP9-DL1 cells. While high levels of IL-7R are present on thymocytes, increased suppressor of cytokine signaling-1 expression blunts IL-7 downstream signaling, resulting in hypo-phosphorylation of proteins in the PI3K-Akt pathway. Consequently, GSK3 remains active and inhibits Notch-1 signaling as observed by decreased Hes-1 and Deltex expression in thymic progenitors. This is the first demonstration that high levels of IL-7 antagonize Notch-1 signaling and suggest that IL-7 may affect T- versus B-lineage choice in the thymus.