The adaptive immune response recognises infection through presentation of pathogen derived peptides in association with MHC to the host T cells. One of the mechanisms which pathogens use to evade this immune response is to down regulate their MHC cell surface expression. Natural Killer (NK) cells are able to detect altered expression of MHC through a number of cell surface receptors leading to target cell lysis. These receptors include the killer immunoglobulin like receptors (KIR), which are also expressed on some effector T cells. In humans, the KIR gene cluster is located on chromosome 19. KIR genes are both polygenic and polymorphic. The KIR gene cluster codes for 15 expressed KIR genes and 2 pseudo genes.
The ligands for KIR receptors are HLA class I molecules. These include HLA-C locus antigens with either Asn (Group 1 HLA-C antigens) or Lys (Group 2 HLA-C antigens) at position 80, the HLA-Bw4 epitope and some HLA-A antigens. KIR receptors binding to HLA class I are either inhibitory or are stimulatory with the overall effect of NK cell interaction with the target cell dependent on the balance between these inhibitory and stimulatory signals. It is thought that the inhibitory KIR’s bind class I with greater affinity than the corresponding activating KIR with the effect that under normal circumstances the inhibitory signal prevails. The ‘missing self’ hypothesis holds that NK cell alloreactivity occurs when the ligand for inhibitory KIR receptors is down regulated or ‘missing’, leading to activation. This however requires that KIR receptors engage their cogent HLA class I molecules during maturation to acquire effector function. NK cells that express only inhibitory KIRs for absent HLA class I molecules are hypo responsive in the non transplant setting.
Inhibitory KIR receptors possess long cytoplasmic tails with immunoreceptor tyrosine based inhibitory motifs (ITIMs). Activating KIR receptors have short cytoplasmic tails that pair with adaptor molecules with immunoreceptor tyrosine based activating motif (ITAMs). The nomenclature for KIR receptors therefore includes an ‘L’ (long tail) for inhibitory KIR’s and an ‘S’ (short tail) for activating KIR’s. The nomenclature also includes ‘P’ for pseudo genes. The inhibitory and activating KIR receptors share sequence and structural similarities in their extracellular domains. KIR’s have either 2 or 3 extracellular immunoglobulin domains and this is reflected in their nomenclature as either ‘2D’ or ‘3D’, giving KIR receptors nomenclature such as KIR2DL1, KIR2DS2 and KIR3DL1, where the final digit indicates the order in which the genes were described.
The KIR genes assemble into haplotypes with two haplotypes described, ‘A’ and ‘B’. The ‘A’ haplotype has only one activating KIR (2DS4), while the ‘B’ haplotype has a higher number of activating KIRs and generally posses more KIRs than the ‘A’ haplotype.
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