Innate or adaptive immunity? The example of natural killer cells

Abstract

Natural killer (NK) cells were originally defined as effector lymphocytes of innate immunity endowed with constitutive cytolytic functions. More recently, a more nuanced view of NK cells has emerged. NK cells are now recognized to express a repertoire of activating and inhibitory receptors that is calibrated to ensure self-tolerance while allowing efficacy against assaults such as viral infection and tumor development. Moreover, NK cells do not react in an invariant manner but rather adapt to their environment. Finally, recent studies have unveiled that NK cells can also mount a form of antigen-specific immunologic memory. NK cells thus exert sophisticated biological functions that are attributes of both innate and adaptive immunity, blurring the functional borders between these two arms of the immune response.

Fig. 1

The biological functions of NK cells. NK cells can recognize a variety of stressed cells in the absence or in the presence of antibodies (blue arrows). NK cell activation triggered by this recognition can lead to the lysis of the target cell and to the production of various cytokines and chemokines depending on the nature of the stimulation. Whereas NK cells are biased to produce IFN-γ in many conditions, there are situations of chronic or systemic inflammation that promote IL-10 secretion. NK can also cross-talk with DC in many different ways, including the NK cell killing of immature DC and the promotion of DC maturation by NK cell–derived IFN-γ and TNF-α, which leads to enhanced antigen presentation to T cells. Through these biological activities, NK cells participate in the shaping of the subsequent immune response; in the depicted example, NK cells boost or dampen macrophage and T cell responses through IFN-γ (green arrows) or IL-10 secretion (red arrows), respectively.

Fig. 2

NK cell receptors. NK cells express many cell surface receptors that can be grouped into activating (green), inhibitory (red), adhesion (blue), cytokine (black) and chemotactic receptors (purple). In addition to MHC class I–specific receptors, other NK cell inhibitory receptors specific for non-MHC ligands also regulate NK cell reactivity (78). Adaptor molecules involved in the signaling cascade downstream of the engagement of activating receptors (green) are also indicated. The list of cell surface molecules involved in the regulation of mouse and human NK cell function is not exhaustive. Unless indicated (h, human; m, mouse), receptors are conserved in both species.

Fig. 3

The dynamic regulation of NK cell effector function. NK cells sense the density of various cell surface molecules expressed at the surface of interacting cells. The integration of these distinct signals dictates the quality and the intensity of the NK cell response. NK cells spare healthy cells that express self-MHC class I molecules and low amounts of stress-induced self molecules (A), whereas they selectively kill target cells “in distress” that down-regulate MHC class I molecules (B) or up-regulate stress-induced self molecules (C). +, activating receptors; −, inhibitory receptors.

Fig. 4

NK cell tuning. Experimental conditions in which NK cells have been shown to adapt to their environment are schematized. In the absence of detection of MHC class I, such as when NK cells lack cognate MHC class I receptors (A) or in MHC class I–deficient hosts (B), NK cells are hyporesponsive at steady state. NK cells are rendered “anergic” by the chronic engagement of various activating receptors such as NKG2D (C), Ly49H in the mouse (D), or KIR2DS1 in humans (E). NK cells can be educated by MHC class I molecules via their cognate inhibitory receptors in trans (F) or in cis (not depicted) and primed by cytokines (G).