CD94/NKG2

CD94/NKG2 is a family of C-type lectin receptors which are expressed predominantly on the surface of NK cells and a subset of CD8+ T-lymphocyte. These receptors stimulate or inhibit cytotoxic activity of NK cells, therefore they are divided into activating and inhibitory receptors according to their function. CD94/NKG2 recognize nonclassical MHC glycoproteins class I (HLA-E in human and Qa-1 molecules in the mouse). CD94/NKG2 is a family of C-type lectin receptors which are expressed predominantly on the surface of NK cells and a subset of CD8+ T-lymphocyte. These receptors stimulate or inhibit cytotoxic activity of NK cells, therefore they are divided into activating and inhibitory receptors according to their function. CD94/NKG2 recognize nonclassical MHC glycoproteins class I (HLA-E in human and Qa-1 molecules in the mouse). CD94/NKG2 family includes seven members: NKG2A, B, C, D, E, F and H. Genes encoding these receptors are clustered in the natural killer complex (NKC) on human chromosome 12 and mouse chromosome 6 together with Clr (C-lectin related) genes. NKG2 receptors are transmembrane proteins type II which dimerize with CD94 molecule. CD94 contains a short cytoplasmic domain and it is responsible for signal transduction. Therefore NKG2 receptors form disulfide bonded heterodimers. NKG2D represent an exception, it is a homodimer. Receptors of CD94/NKG2 family bind nonclassical MHC glycoproteins class I (HLA-E in human and Qa-1 molecules in the mouse). Nonclassical MHC glycoproteins class I are structurally similar to classical MHC class I molecules, but they present mainly peptides derived from the signal peptides of MHC class I. Therefore NK cells can indirectly monitor the expression of classical MHC class I molecules through the interaction of CD94/NKG2 with HLA-E (Qa-1) and HLA-E (Qa-1) themselves as well. During cytomegalovirus infection, virus peptides are presented on HLA-E and NK cells that express the CD94/NKG2C receptor can specifically recognise these virus peptides, which results in activation, expansion, and differentiation of adaptive NK cells. NKG2D constitutes an exception. Besides the fact that it is a homodimer, it associates with adaptor molecule DAP10 and its amino acid sequence is identical in only 28% in comparison with other CD94/NKG2 family members, NKG2D binds MHC class I homologues MICA (MHC class I polypeptide-related sequence A), MICB and ULBP (UL-16 binding protein) in human. MICA and MICB are expressed on the surface of epithelial and endothelial cells. The expression of these NKG2D ligands is higher in case of cellular stress, e.g. tumor disease or inflammation. This activates NK cells and triggers their cytotoxicity. ULBP is expressed constitutively in different tissues and it stimulates NK cells to secrete cytokines and chemokines. Mouse NKG2D binds H-60 molecules, five variants of Rae1 protein (Retinoic acid transcript 1) and Mult1 (mouse ULBP-like transcript 1). H-60 and Rae1 are structurally similar to MHC glycoproteins class I and their expression is increased in tumor cells. This leads to NK cell activation and IFN-γ production, which stimulates cells of innate immunity.