HIF1α is required for NK cell metabolic adaptation during virus infection.
HIF1α is required for NK cell metabolic adaptation during virus infection.
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DOI：
10.7554/elife.68484
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发表时间：
2021-08-16
期刊：
影响因子：
7.7
通讯作者：
Yokoyama WM
中科院分区：
文献类型：
--
作者：
Victorino F;Bigley TM;Park E;Yao CH;Benoit J;Yang LP;Piersma SJ;Lauron EJ;Davidson RM;Patti GJ;Yokoyama WM
自然杀伤（NK）细胞对于早期保护免受病毒感染至关重要，并且必须在代谢上适应激活的能量需求。在此，我们发现代谢衔接低氧诱导因子-1 α（HIF 1 α）的上调是小鼠巨细胞病毒（MCMV）体内感染过程中小鼠NK细胞的一个特征。HIF 1 α缺陷型NK细胞无法控制病毒载量，导致发病率增加。未发现HIF 1 αKO NK细胞的效应功能缺陷;然而，它们的数量显著减少。在体内感染和体外细胞因子刺激期间，HIF 1 α的缺失不影响NK细胞增殖。相反，我们发现HIF 1 α缺陷型NK细胞在体外细胞因子刺激期间表现出促凋亡蛋白Bim表达增加，葡萄糖代谢受损。类似地，在MCMV感染期间，HIF 1 α缺陷型NK细胞上调Bim并具有增加的caspase活性。因此，NK细胞需要HIF 1 α依赖性代谢功能来抑制Bim表达并维持细胞数量以获得最佳病毒应答。
Natural killer (NK) cells are essential for early protection against virus infection and must metabolically adapt to the energy demands of activation. Here, we found upregulation of the metabolic adaptor hypoxia-inducible factor-1α (HIF1α) is a feature of mouse NK cells during murine cytomegalovirus (MCMV) infection in vivo. HIF1α-deficient NK cells failed to control viral load, causing increased morbidity. No defects were found in effector functions of HIF1αKO NK cells; however, their numbers were significantly reduced. Loss of HIF1α did not affect NK cell proliferation during in vivo infection and in vitro cytokine stimulation. Instead, we found that HIF1α-deficient NK cells showed increased expression of the pro-apoptotic protein Bim and glucose metabolism was impaired during cytokine stimulation in vitro. Similarly, during MCMV infection HIF1α-deficient NK cells upregulated Bim and had increased caspase activity. Thus, NK cells require HIF1α-dependent metabolic functions to repress Bim expression and sustain cell numbers for an optimal virus response.