Unravelling natural killer cell function: triggering and inhibitory human NK receptors

Abstract

Natural killer (NK) cells represent a highly specialized lymphoid population characterized by a potent cytolytic activity against tumor or virally infected cells. Their function is finely regulated by a series of inhibitory or activating receptors. The inhibitory receptors, specific for major histocompatibility complex (MHC) class I molecules, allow NK cells to discriminate between normal cells and cells that have lost the expression of MHC class I (e.g., tumor cells). The major receptors responsible for NK cell triggering are NKp46, NKp30, NKp44 and NKG2D. The NK-mediated lysis of tumor cells involves several such receptors, while killing of dendritic cells involves only NKp30. The target-cell ligands recognized by some receptors have been identified, but those to which major receptors bind are not yet known. Nevertheless, functional data suggest that they are primarily expressed on cells upon activation, proliferation or tumor transformation. Thus, the ability of NK cells to lyse target cells requires both the lack of surface MHC class I molecules and the expression of appropriate ligands that trigger NK receptors.

Figure 1

Activating NK receptors and coreceptors and their cellular ligands. This figure illustrates the molecular structure of the NK receptors NKp46, NKp30, NKp44 and NKG2D as well as of the NK coreceptors 2B4, NTB-A, DNAM-1 and NKp80. Their interaction with signaling polypeptides or with relevant cytoplasmic molecules is also shown. The known cellular ligands are illustrated in a simplified form.

Figure 2

Altered function of 2B4 and NTBA surface receptors in XLP. In normal NK cells (left), both 2B4 and NTBA function as coreceptors cooperating with triggering receptors (here NKp46 is shown) to induce optimal NK cell activation upon interaction with EBV-infected B cells. B-EBV express high levels of CD48, the ligand for 2B4, as well as still undefined ligands for NKp46 and NTBA. NK cell triggering via 2B4 (upon interaction with CD48) requires the recruitment of SAP, an intracytoplasmic polypeptide, which likely prevents the generation of inhibitory signals mediated by SHP-1 phosphatase. The triggering signals delivered via NKp46 and amplified by 2B4 and NTBA lead to NK cell activation and induction of cytolysis of B-EBV cells. The molecular defect in XLP patients is represented by the lack of functional SAP molecules. As a consequence, the lack of their association with 2B4 and NTBA leads to recruitment and activation of SHP-1. This in turn extinguishes the triggering signals delivered via NKp46 or other activating receptors. As a result, NK cells fail to lyse EBV-infected B cells and/or to release cytokines relevant in the control of viral infection. In over 70% of patients, the clinical outcome is represented by fulminant infectious mononucleosis and death.