Iron deficiency in people with obesity drives defective Natural Killer cell mitochondrial fitness and function

Natural killer (NK) cells are a population of innate effector lymphocytes, involved in host-defences against viral infections and cancer. Upon activation, NK cells can produce a milieu of cytotoxic molecules and cytokines, which can directly target infected and transformed cells, but also amplify an immune response. Metabolic rewiring underpins NK cell effector functionality, providing the required signals, energy and biointermediates to support their immune responses. Obesity is associated with significant defects in the functionality of human NK cells, especially in the periphery. Dysregulated cellular metabolism has been demonstrated to be a major mechanistic driver of the reported defects. However, how obesity links to defective NK cell metabolism and functionality remains unclear. Iron deficiency is a common co-morbidity in people living with obesity (PWO). Recent studies have highlighted the importance for iron in host immunity, with murine models of iron deficiency resulting in defective cellular metabolism and function. We hypothesized that obesity-driven iron deficiency might underpin the reported defects in NK cells. Our data demonstrates that in response to cytokine stimulation, healthy human NK cells utilize iron to support their metabolic activity and cytokine responses. In a cohort of PWO, we demonstrate alterations in NK cell metabolism, mitochondrial fitness and cytokine production. Furthermore, upon stratification into PWO with normal iron status versus low iron status, we show the observed obesity-related defects in NK cell metabolism, mitochondrial fitness and cytokine production are concentrated in the PWO with low-iron status. Collectively, our data highlights the importance of iron for human NK cell responses and provides evidence that obesity-driven defects in NK cell metabolism and function are linked in part to altered iron availability.