Natural Killer Cell Receptors: Human Target Cell – NK Cell Ligand-Receptor Interactions

Natural killer (NK) cells are innate lymphocytes that play a crucial role in the early response to infection or malignant transformation. Under these conditions, NK cells are activated and promote target cell death through the release of cytolytic granules. In addition, they secrete cytokines that regulate the functions of other immune cells. The activity of NK cells is controlled by the relative balance of signals received from cell surface receptors that deliver either activating or inhibitory signals. Under normal physiological conditions, NK cell activation is inhibited by ligands expressed on healthy cells that engage inhibitory receptors on NK cells. A reduction in the expression of these ligands, which occurs in stressed cells, can lead to NK cell activation. NK cells can also be activated by the up-regulation of stress-induced ligands that typically occurs in response to infection or malignant transformation. Due to their ability to specifically attack and eliminate stressed cells, while maintaining tolerance to normal, healthy cells, NK cells are being investigated as potential anti-cancer agents.

NK cells express multiple receptors that are responsible for initiating activating or inhibitory signals. Activating NK cell receptors include members of the human Killer Immunoglobulin-like Receptor (KIR) family or the mouse Ly49 family, CD94-NKG2C/E/H heterodimeric receptors, NKG2D, natural cytotoxicity receptors such as NKp30, NKp44, and NKp46, and the nectin/nectin-like binding receptors DNAM-1/CD226 and CRTAM. In contrast, receptors that inhibit NK cell activation are important for self-tolerance. This group of receptors includes alternate members of the human KIR family or the mouse Ly49 family, CD94-NKG2A, and the nectin/nectin-like binding receptors TIGIT and CD96. In addition to these receptor families, there are multiple other receptors expressed by natural killer (NK) cells that regulate their activation. SLAM family receptors including 2B4/CD244, CRACC/SLAMF7, and NTB-A/SLAMF6, as well as Fc gamma RIIIA/CD16a, CD27, CD100/Semaphorin 4D, and CD160 are additional NK cell activating receptors, while the sialic acid-binding Siglecs (Siglec-3, -7, and -9), ILT2/LILRB1, KLRG1, LAIR-1, CD161/NKR-P1A, and CEACAM-1 are additional NK cell inhibitory receptors. Although ligands for many of these receptors are still being investigated, a variety of viral, tumor cell-associated, and cellular ligands have been identified and are depicted in the schematic.

To learn more, explore the following Natural killer cell-related resources:

Natural Killer Cell Research Area

Natural Killer Cell Markers

Immune Checkpoint Targets eBook