Natural Killer Group 2 Member D, Its Ligands, and Liver Disease: Good or Bad?

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Liver lymphocytes are enriched in natural killer (NK) cells, which play an important role in host defenses against microbial infection and tumor transformation in the liver.1 Generally, it is believed that the cytotoxicity of NK cells against target cells is controlled by the opposing signals from inhibitory and stimulatory receptors on NK cells interacting with their corresponding ligands expressed on target cells.2, 3 The NK cell inhibitory receptors include CD94/NKG2, Ly49A, and the Ig-like killer inhibitory receptor, which interact with inhibitory ligands (eg, self MHC class I molecules) expressed on target cells and inactivate NK cell function. The stimulatory receptors include NKp46, NKp30, NKp44, NKG2D, and DNAX accessory molecule 1 (CD226). Among these, the best-defined receptor is NKG2D (natural-killer group 2, member D), a highly conserved C-type lectin-like membrane glycoprotein that is also one of the major activating receptors on NK cells. 2, 3 Expressed on essentially all NK cells, as well as on γδ-TcR+ T cells and αβ-TcR+ CD8+ T cells, NKG2D is found in both humans and mice. In humans, known NKG2D ligands include major histocompatiblity complex (MHC) class I-related chain A and B (MICA/B) and UL16-binding protein 1, 2, 3, 4 (ULBP1, 2, 3, 4). In mice, known NKG2D ligands include retinoic acid early inducible gene-1 (RAE-1), minor histocompatibility H60, and murine UL16-binding protein-like transcript 1 (MULT1). The expression of these NKG2D ligands is usually upregulated on microbe-infected, transformed, or stressed cells. The interaction between these ligands and NKG2D on NK cells leads to NK cell activation, thereby playing an important role in host defenses against viral infection and tumor transformation. In addition, CD8+ T cells also express NKG2D, which serves as a co-stimulatory signal to activate CD8+ T cells. 2, 3