Maintaining the Balance: Regulation of NK Cell Activity

Abstract

Natural Killer (NK) cells, integral components of the innate immune system, play a crucial role in the protection against intracellular threats. Their cytotoxic power requires that activation is tightly controlled, and in this, they take a unique position within the immune system. Rather than depending on the engagement of a single activating receptor, their activation involves a delicate balance between inhibitory and activating signals mediated through an array of surface molecules. Only when this cumulative balance surpasses a specific threshold do NK cells initiate their activity. Remarkably, the activation threshold of NK cells remains robust even when cells express vastly different repertoires of inhibitory and activating receptors. These threshold values seem to be influenced by NK cell interactions with their environment during development and after release from the bone marrow. Understanding how NK cells integrate this intricate pattern of stimuli is an ongoing area of research, particularly relevant for cellular therapies seeking to harness the anti-cancer potential of these cells by modifying surface receptor expression. In this review, we will explore some of the current dogmas regarding NK cell activation and discuss recent literature addressing advances in our understanding of this field.

Keywords: NK cells; activating receptors; activation; inhibitory receptors.

Figure 1

NK cell activation and immune regulation: The binding of an activating receptor to its ligand causes a shift in the balance between activating and inhibitory receptors, resulting in NK cell activation. This activation is further enhanced by the cytokines IL-12 and IL-18, which are produced by dendritic cells and macrophages. Once activated, NK cells can eliminate target cells through the release of lytic granules containing granzyme B, which induce target cell death. Moreover, NK cells secrete cytokines such as IFN-γ and TNF-α, which help modulate the functions of other innate and adaptive immune cells.

Figure 2

Regulation of NK cell activity: NK cell activity is regulated at multiple levels, both during development and in the periphery. During development, NK cells undergo classical NK cell education (a) as well as specific education that establishes a threshold for activating receptors such as NKp46 (b). In the periphery, their activity is tightly controlled through mechanisms involving paired receptors (c) and is further safeguarded by the balance system (d).

Figure 3

Adaptation of the NK Cell Receptor Profile and Sensitivity Following the Loss of an Activating/Inhibitory Receptor: When an activating receptor is lost, NK cells modify their receptor profile to sustain the “balance system” and preserve their sensitivity. This modification may include the downregulation of some inhibitory receptors and/or the upregulation of particular activating receptors (a). Moreover, the loss of one receptor can be offset by the increased responsiveness of another receptor (b).