NKG2D and Its Ligands: "One for All, All for One"

Abstract

The activating receptor NKG2D is peculiar in its capability to bind to numerous and highly diversified MHC class I-like self-molecules. These ligands are poorly expressed on normal cells but can be induced on damaged, transformed or infected cells, with the final NKG2D ligand expression resulting from multiple levels of regulation. Although redundant molecular mechanisms can converge in the regulation of all NKG2D ligands, different stimuli can induce specific cellular responses, leading to the expression of one or few ligands. A large body of evidence demonstrates that NK cell activation can be triggered by different NKG2D ligands, often expressed on the same cell, suggesting a functional redundancy of these molecules. However, since a number of evasion mechanisms can reduce membrane expression of these molecules both on virus-infected and tumor cells, the co-expression of different ligands and/or the presence of allelic forms of the same ligand guarantee NKG2D activation in various stressful conditions and cell contexts. Noteworthy, NKG2D ligands can differ in their ability to down-modulate NKG2D membrane expression in human NK cells supporting the idea that NKG2D transduces different signals upon binding various ligands. Moreover, whether proteolytically shed and exosome-associated soluble NKG2D ligands share with their membrane-bound counterparts the same ability to induce NKG2D-mediated signaling is still a matter of debate. Here, we will review recent studies on the NKG2D/NKG2D ligand biology to summarize and discuss the redundancy and/or diversity in ligand expression, regulation, and receptor specificity.

Keywords: NK cells; NKG2D ligands; NKG2D receptor; cancer; virus infection.

Figure 1

Functional consequences of the interaction of NKG2D with different ligand/allelic variants. (A) Transmembrane MICA and GPI-linked ULBP2 ligands result equally able to trigger Vav1 and PI3K activation and to induce NK cell cytotoxic function. However, a stronger receptor internalization and lysosomal degradation due to the activation of the ubiquitin pathway was observed upon MICA engagement. Whether Cbl is the ubiquitin ligase regulating NKG2D/DNAX-activating protein 10 ubiquitination and whether ULBP2 ligand is able to activate NKG2D-mediated signals from endosomal compartment is not clear (dashed arrows). (B) MICA-129Met, which binds to NKG2D with higher avidity compared with MICA-129Val allele, induces stronger Src phosphorylation, thus triggering both NK cell and CD8⁺ T cell effector functions with higher efficiency. Concomitantly, a higher extent of NKG2D down-modulation is also induced upon MICA-129Met allele engagement. (C) The rigid and stable binding to NKG2D of the high-affinity ULBP0602 variant impairs its ability to induce Ca⁺⁺ flux and effector functions in NK cell and CD8⁺ T cells as well as NKG2D down-modulation. As consequence, ULBP0602 engagement results less efficient compared with the low affinity variant ULBP0601.