CD56-mediated activation of human natural killer cells is triggered by Aspergillus fumigatus galactosaminogalactan

by Linda Heilig, Fariha Natasha, Nora Trinks, Vishukumar Aimanianda, Sarah Sze Wah Wong, Thierry Fontaine, Ulrich Terpitz, Lea Strobel, François Le Mauff, Donald C. Sheppard, Sascha Schäuble, Oliver Kurzai, Kerstin Hünniger, Esther Weiss, Mario Vargas, P. Lynne Howell, Gianni Panagiotou, Sebastian Wurster, Hermann Einsele, Juergen Loeffler

Invasive aspergillosis causes significant morbidity and mortality in immunocompromised patients. Natural killer (NK) cells are pivotal for antifungal defense. Thus far, CD56 is the only known pathogen recognition receptor on NK cells triggering potent antifungal activity against Aspergillus fumigatus. However, the underlying cellular mechanisms and the fungal ligand of CD56 have remained unknown. Using purified cell wall components, biochemical treatments, and ger mutants with altered cell wall composition, we herein found that CD56 interacts with the A. fumigatus cell wall carbohydrate galactosaminogalactan (GAG). This interaction induced NK cell activation, degranulation, and secretion of immune-enhancing chemokines and cytotoxic effectors. Supernatants from GAG-stimulated NK cells elicited antifungal activity and enhanced antifungal effector responses of polymorphonuclear cells. In conclusion, we identified A. fumigatus GAG as a ligand of CD56 on human primary NK cells, stimulating potent antifungal effector responses and activating other immune cells.