NK Cell Disfunction in Atopic Dermatitis: A Missing Link Between Type 2 Inflammation, Microbial Dysbiosis and Antiviral Immunity

Atopic dermatitis (AD) is a prevalent chronic inflammatory skin disorder driven by epidermal barrier defects and dysregulated Th2 cell responses. While therapies primarily address adaptive immunity, the role of Natural Killer (NK) cells remains underappreciated. This review analyzes NK cell dysfunctions in AD pathogenesis, evaluating their contributions to compromised skin immunity, microbial dysbiosis, and secondary infections. Accumulating evidence reveals a systemic deficiency of mature, cytotoxic CD56dim and NKp80+ NK cell subsets in peripheral blood, correlating with disease severity. Within the cutaneous microenvironment, Staphylococcus aureus subverts defenses by utilizing leukocidins to lyse mature NK cells, while superantigens drive an aberrant, pro-inflammatory CD57−NKG2+ phenotype, exacerbating inflammation. Furthermore, localized exhaustion of functional NK cells and failure to produce interferon-gamma directly explains AD patients’ unique susceptibility to severe viral complications like eczema herpeticum. Importantly, treatments such as dupilumab and gut microbiota transplantations demonstrate that these NK cell aberrations are reversible, shifting immunity toward a normalized regulatory state. In conclusion, the NK cell compartment represents a vital regulatory axis bridging innate and adaptive immunity. Targeting this axis, particularly through IL-15 superagonists, offers a promising therapeutic frontier to suppress type 2 inflammation and restore antimicrobial defenses.