NK cells in childhood obesity are activated, metabolically stressed, and functionally deficient
NK cells in childhood obesity are activated, metabolically stressed, and functionally deficient
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DOI：
10.1172/jci.insight.94939
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发表时间：
2017-12-21
期刊：
影响因子：
8
通讯作者：
O'Shea, Donal
中科院分区：
文献类型：
--
作者：
Tobin, Laura M.;Mavinkurve, Meenal;O'Shea, Donal
儿童肥胖是一个主要的全球性问题，目前有超过5000万儿童被列为肥胖。肥胖与许多慢性炎症性疾病的发展有关，包括2型糖尿病和多种癌症。NK细胞是天然效应细胞的一个亚群，在调节脂肪组织和抗肿瘤免疫中起重要作用。NK细胞可以自发地杀死转化的细胞，并通过产生细胞因子来协调随后的免疫应答。我们研究了肥胖对一组肥胖儿童NK细胞的影响，并与健康体重的儿童进行了比较。我们证明了儿童肥胖患者外周NK细胞频率的降低，并与体重指数和胰岛素抵抗呈负相关。与正常体重儿童的NK细胞相比，我们发现肥胖儿童的NK细胞活化和代谢（PD-1、mTOR活化、ECAR和线粒体ROS）增加，沿着对刺激的反应能力降低，最终导致功能丧失（增殖和肿瘤溶解）。总的来说，我们发现肥胖儿童的NK细胞被激活，代谢紧张，失去了履行其基本职责的能力。与儿童肥胖症中NK细胞频率的降低相结合，这表明对抗肿瘤免疫的负面影响存在于肥胖症生命过程的早期，并且肯定是在明显恶性肿瘤发展之前多年。
Childhood obesity is a major global concern, with over 50 million children now classified as obese. Obesity has been linked to the development of numerous chronic inflammatory diseases, including type 2 diabetes and multiple cancers. NK cells are a subset of innate effector cells, which play an important role in the regulation of adipose tissue and antitumor immunity. NK cells can spontaneously kill transformed cells and coordinate subsequent immune responses through their production of cytokines. We investigated the effect of obesity on NK cells in a cohort of obese children, compared to children with a healthy weight. We demonstrated a reduction in peripheral NK cell frequencies in childhood obesity and inverse correlations with body mass index and insulin resistance. Compared with NK cells from children with normal weight, we show increased NK cell activation and metabolism in obese children (PD-1, mTOR activation, ECAR, and mitochondrial ROS), along with a reduced capacity to respond to stimulus, ultimately leading to loss of function (proliferation and tumor lysis). Collectively we show that NK cells from obese children are activated, metabolically stressed, and losing the ability to perform their basic duties. Paired with the reduction in NK cell frequencies in childhood obesity, this suggests that the negative effect on antitumor immunity is present early in the life course of obesity and certainly many years before the development of overt malignancies.