Progressive accumulation of hyperinflammatory NKG2D lowNK cells in early life defines a novel endotype of severe atopic dermatitis

Abstract

Abstract Atopic dermatitis (AD) is a chronic inflammatory skin disease that often precedes the development of food allergy, asthma, and allergic rhinitis. The prevailing paradigm holds that a reduced frequency and function of natural killer (NK) cell contributes to AD pathogenesis, yet the underlying mechanisms and contributions of NK cells to allergic co-morbidities remain ill-defined. Herein, longitudinal analysis of circulating NK cells in a well-defined early life cohort of children with AD revealed a progressive accumulation of NK cells with low expression of the activating receptor NKG2D that was linked to more severe AD and sensitivity to allergens. This was most notable in children co-sensitized to food and aero allergens, a risk factor for development of asthma. Importantly, low expression of NKG2D on NK cells was paradoxically associated with depressed cytolytic function but exaggerated release of the proinflammatory cytokine TNF-a. These observations provide important new insights into a potential pathophysiological mechanism of atopic march involving altered NK cell functional responses and define a novel endotype of severe AD. 5U19AI70235 (GKKH, JBM, LJM); American Heart Association (DEO); R01AI148080, R01AR073228 (SNW), 5T32GM063483 (SBD)