Candida species-dependent release of IL-12 by dendritic cells induces different levels of NK cell stimulation

Candida albicans and Candida glabrata are the two most prevalent Candida species causing bloodstream infections. Patterns of innate immune activation triggered by the two fungi differ considerably. To analyze human natural killer (NK) cell activation by both species, we performed ex vivo whole-blood infection assays and confrontation assays with primary human NK cells (NKC). C. albicans was a stronger activator for isolated human NKC than C. glabrata. In contrast, activation of blood NKC - characterized by an up-regulated surface exposure of early activation antigen CD69 and death receptor ligand TRAIL as well as IFN-gamma secretion was more pronounced during C. glabrata infection. NK cell activation in blood is mediated by humoral mediators released by other immune cells and does not depend on direct activation by fungal cells. Cross-talk between Candida-confronted monocyte-derived dendritic cells (moDC) and NKC resulted in the same NK activation phenotype like NKC in human blood. Blocking experiments and cytokine substitution identified IL-12 as a critical mediator in regulation of primary NKC by moDC-derived cytokines that was also partially responsible for stimulation of blood NKC, especially with regard to higher IFN-gamma levels released upon C. glabrata infection.