The Insulin Receptor Plays a Critical Role in T Cell Function and Adaptive Immunity
The Insulin Receptor Plays a Critical Role in T Cell Function and Adaptive Immunity
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DOI：
10.4049/jimmunol.1601011
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发表时间：
2017-03-01
影响因子：
4.4
通讯作者：
Reichardt, Holger M.
中科院分区：
文献类型：
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作者：
Fischer, Henrike J.;Sie, Christopher;Reichardt, Holger M.
T细胞激活是一个需要能量的过程，由葡萄糖消耗增加和胰岛素受体（INSR）的上调所驱动。在本文中，我们报道了在诱导性敲除大鼠中沉默INSR会损害选择性T细胞功能，但不会损害胸腺细胞的发育。在缺乏INSR的情况下，活化CD4(+) T细胞中的葡萄糖转运和糖酵解受到损害，这与细胞内信号通路的改变有关。所观察到的代谢缺陷与细胞因子产生、增殖和迁移减少以及CD4(+) T细胞凋亡增加相吻合。在这些条件下，CD8(+) T细胞对同种抗原的细胞毒性也减弱，而调节性T细胞的频率和抑制能力不受影响。观察到的损伤在体内被证明是决定性的，因为INSR的沉默减轻了急性移植物抗宿主病和多发性硬化症动物模型的临床症状。综上所述，我们的研究结果表明，激活后T细胞上INSR的上调是有效的适应性免疫所必需的。
T cell activation is an energy-demanding process fueled by increased glucose consumption and accompanied by upregulation of the insulin receptor (INSR). In this article, we report that silencing the INSR in inducible knockdown rats impairs selective T cell functions but not thymocyte development. Glucose transport and glycolysis in activated CD4(+) T cells were compromised in the absence of the INSR, which was associated with alterations in intracellular signaling pathways. The observed metabolic defects coincided with reduced cytokine production, proliferation, and migration, as well as increased apoptosis of CD4(+) T cells. The cytotoxicity of CD8(+) T cells in response to alloantigens was also diminished under these conditions, whereas the frequency and suppressive capacity of regulatory T cells were unaffected. The observed impairments proved to be decisive in vivo because silencing of the INSR attenuated clinical symptoms in animal models of acute graft-versus-host disease and multiple sclerosis. Taken together, our results suggest that upregulation of the INSR on T cells following activation is required for efficient adaptive immunity.