KIR2DS4

KIR2DS4 is the only activating KIR gene carried by haplotype A, with 12 alleles, of which 9 alleles have nucleotide changes in the coding region: 2DS4*00101, *00102 and *00103 encode intact cell surface Receptor KIR2DS4, and the 2DS4*003.004, 006, 007, 008, and 009 alleles are deleted by a 22 bp base in exon 5, resulting in a shift in the reading frame and formation of a truncated KIR2DS4 receptor. Due to the loss of the transmembrane and cytoplasmic domains, the body cannot be anchored to the cell membrane, resulting in a soluble, non-functional variant, KIR1D. Different human races have different KIR2DS4 allele frequencies. The proportion of KIR2DS4 and KIR1D gene frequencies is about 2:117-193 for yellow races (including Chinese Han, Japanese, and Korean), and the KIR1D gene is predominant for Caucasians. The KIR2DS4 receptor has no immunoreceptor tyrosine-based inhibitory motif (ITIM) in the cytoplasmic domain but contains a positively charged lysine residue in the transmembrane region, which can be immunologically regulated with other receptors. Molecular tyrosine-based activation motif (ITAM) molecules such as DNAX-associated protein (DAP) 12, or killer cell activating receptor-associated protein (killer cell activating receptor-associated protein, KARAP) non-covalent binding, phosphorylation of DAP12, Sky tyrosine kinase, phospholipase C, etc., activates the mitogen-activated protein kinase (MAPK) cascade, causing NK cell activation.
At present, the knowledge of the corresponding ligands of KIR2DS4 is limited. Studies have shown that KIR2DS4 ligands are mainly HLA-A* 11, partial HLA-C1 and HLA-C2 and unrecognized melanoma antigens. Since KIR1D encodes a soluble molecule, KIR1D blocks the ligands of other receptors on KIR2DS4 or certain cells (such as T cells, NK cells), or acts as an inducer to clear soluble HLA, interfering with NK cell function. Studies have also shown that KIR1D molecules may function through ligand interaction with KIR2DS4. The KIR1D protein may play a paracrine function on cells expressing its ligand or may play a membrane receptor competing for function on the expression of a crossover ligand.