Natural killer cells from children with obesity exhibit a persistent ‘trained’ response to influenza

Children and adults living with obesity have more severe influenza A virus (IAV) infection, but the underlying mechanisms are unclear. Natural killer (NK) cells play a key role in the innate immune responses to IAV and clearance of IAV-infected cells. ‘Trained immunity’ of NK cells (and other innate immune cells) refers to an initial stimulus (i.e. obesity) inducing metabolic and epigenetic changes that make these cells hyperinflammatory upon restimulation (i.e. with IAV). Here, we tested whether obesity in children induces trained immunity in NK cells. We have show that NK cells from children with obesity have a hyperinflammatory ‘trained’ phenotype, with increased expression of activation markers TLR2, CCR2, TLR4, HLA-DR and CD11b compared to children without obesity. Furthermore, we have demonstrate that NK cells from children with obesity have a heightened ex vivo IFN-γ response to stimulation with IAV (A/Auckland/4/2009, H1N1 and HKx31, H3N2) and epigenetic changes consistent trained immunity. A decrease in BMI z-score following weight-management was not associated with a reduction in the IFN-γ response, suggesting that weight loss is not sufficient to normalise NK cell function. Better understanding of obesity-related immune modulation is critical for development of new therapeutic strategies and improving outcomes in future IAV pandemics