852 Natural Killer Cell Deficiency Reveals a Novel Immunotherapy Strategy for Atopic Dermatitis

Atopic dermatitis (AD) is a widespread, chronic skin disease associated with aberrant allergic inflammation. While current treatments involve either broad or targeted immunosuppression strategies, enhancing aspects of the immune system to control disease remains largely untested. We demonstrate that patients with AD harbor a blood natural killer (NK) cell deficiency that has both diagnostic value and improves with therapy. Multidimensional CyTOF analysis and RNA-seq profiling of patients' peripheral blood NK cells revealed subset-level changes associated with activation-induced cell death. Both pharmacologic and genetic NK cell depletion in mice resulted in enhanced type 2 inflammation in the skin, characterized by increased group 2 innate lymphoid cells (ILC2s) and eosinophils, suggesting that NK cells play a critical immunoregulatory role. Based on these findings, we employed an NK cell-boosting IL-15 superagonist and observed marked improvement in AD-like disease in mice. These findings reveal a previously unrecognized role for NK cells and IL-15 superagonism, currently in development for cancer immunotherapy, as a novel immunotherapeutic strategy for AD.