Twenty years ago, R. Steinman and colleagues established that dendritic cells (DCs) have unique capacities to prime naive T cells and that DC maturation is the checkpoint for the initiation of adaptive immune responses (1–3). In the mid-1990s, C. Janeway pointed out the pivotal role of innate effectors in dictating adaptive immune responses while few researchers wondered why antigens were much more immunogenic for the specific immune system when applied with “adjuvants” that stimulated innate immunity (4). DC “maturation” appears to be the cornerstone between innate and cognate immunity, but what regulates DC maturation? DCs are sensors of infection and danger (5) and pathways leading to DC activation involve at least toll like receptors and/or proinflammatory cytokine and chemokine receptors (4, 5). However, in non-microbial scenarios such as tumorigenesis, transplantation, or atopy, DC activation might be regulated through other mechanisms whereby a third party cell could convey stress signals to DCs. The activated NK cell could be this third party cell, capable of directly triggering DC maturation (6, 7). In this issue of The Journal of Experimental Medicine, three articles shed some light on the regulatory role of NK cells on the control of DC functions (6–8).

The relevance of innate effectors such as NK cells in resistance to herpes viridae–related infections (9) and tumors (10) is being established. NK cell effector functions are regulated by the balance of activating and inhibitory signals transmitted by membrane receptors that recognize ligands on the cell surface of potential target cells (11–13). But which mechanisms contribute to the “priming” phase of NK cell activation? While so far, experimental model systems exploring NK cell recognition patterns used IL-2, a lymphokine downstream of T cell activation, there is a role for NK cells early on, before cognate T cell activation for the control of MCMV viral infections (9, 14, 15). It was proposed by Fernandez et al.(16) in a mouse model that DCs could act on the priming arm of innate immunity by triggering NK cell effector functions in vitro and in vivo in the setting of a tumor. In line with this observation, bone