NK cells in childhood obesity are activated, metabolically stressed, and functionally deficient
Laura M. Tobin, Meenal Mavinkurve, Eirin Carolan, David Kinlen, Eoin C. O’Brien, Mark A. Little, David K. Finlay, Declan Cody, Andrew E. Hogan, Donal O’Shea
Laura M. Tobin, Meenal Mavinkurve, Eirin Carolan, David Kinlen, Eoin C. O’Brien, Mark A. Little, David K. Finlay, Declan Cody, Andrew E. Hogan, Donal O’Shea
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Research Article Immunology Metabolism

NK cells in childhood obesity are activated, metabolically stressed, and functionally deficient

Abstract

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.

Authors

Laura M. Tobin, Meenal Mavinkurve, Eirin Carolan, David Kinlen, Eoin C. O’Brien, Mark A. Little, David K. Finlay, Declan Cody, Andrew E. Hogan, Donal O’Shea

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Figure 3

NK cells from obese children display increased mTORC1 activity, ECAR, and mitochondrial ROS.

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NK cells from obese children display increased mTORC1 activity, ECAR, an...
(A) Bar graph detailing the expression (MFI) of Glut-1 by NK cells from lean and obese children (n = 10 obese). (B and C) Representative histogram and bar graphs showing basal or stimulated 2-NBDG uptake by NK cells isolated from lean and obese children. The numbers represent the MFI for the histograms on which they are displayed, the black corresponds to leans as per the histogram and grey represents obese MFI. (D) Representative histograms and (E) bar graphs detailing MFI of phosphorylation of ribosomal S6 protein (pS6) expression (mTORC1 activity) in NK cells from lean or obese children. Expression of pS6 was measured in resting NK cells (basal) and cytokine-stimulated NK cells after 4 hours or 18 hours (n = 5). (F) Bar graph showing the extracellular acidification rate (ECAR) of basal or stimulated NK cells from lean or obese children (n = 4). (G) Bar graph showing the mitochondrial mass (MitoTracker Green) of NK cells from lean and obese children. (H) Representative histogram showing mitochondrial ROS (MitoSOX) MFI in NK cells from a lean and an obese child (n = 9 obese). The numbers represent MFI for the histograms. The black font represents lean NK cell mitosox MFI value and grey is the obese. (I) Bar graph showing mitochondrial ROS levels (MFI) in NK cells from lean and obese children. Data are representative of a minimum of 10 independent experiments, unless otherwise noted. Statistical comparisons using Student’s t test or ANOVA with multiple comparisons for groups of 3 or more data sets. *P < 0.05.