Blood natural killer cell deficiency reveals an immunotherapy strategy for atopic dermatitis
Madison R. Mack, Jonathan R. Brestoff, Melissa M. Berrien-Elliott, Anna M. Trier, Ting-Lin B. Yang, Matthew McCullen, Patrick L. Collins, Haixia Niu, Nancy D. Bodet, Julia A. Wagner, Eugene Park, Amy Xu, Fang Wang, Rebecca Chibnall, Carrie Heffington, Friederike Kreisel, David J. Margolis, David Sheinbein, Paola Lovato, Éric Vivier, Marina Cella, Marco Colonna, Wayne M. Yokoyama, Eugene M. Oltz, Todd A. Fehniger, Brian Kim
Abstract
Atopic dermatitis (AD) is a widespread, chronic skin disease associated with aberrant allergic inflammation. Current treatments involve either broad or targeted immunosuppression strategies. However, enhancing the immune system to control disease remains untested. We demonstrate that patients with AD harbor a blood natural killer (NK) cell deficiency that both has diagnostic value and improves with therapy. Multidimensional protein and RNA profiling revealed subset-level changes associated with enhanced NK cell death. Murine NK cell deficiency was associated with enhanced type 2 inflammation in the skin, suggesting that NK cells play a critical immunoregulatory role in this context. On the basis of these findings, we used an NK cell-boosting interleukin-15 (IL-15) superagonist and observed marked improvement in AD-like disease in mice. These findings reveal a previously unrecognized application of IL-15 superagonism, currently in development for cancer immunotherapy, as an immunotherapeutic strategy for AD.