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Chapter 140 : Human Natural Killer Cell Receptors
Regulation of natural killer (NK) cytolytic activity is a function of engagement of one or more NK surface receptors that may be activating or inhibitory. Two of the primary sets of receptors present on human NK cells are called the killer immunoglobulin (Ig)-like receptors (KIR; previously known as the killer inhibitory receptors) and the CD94/NKG2 lectin-like receptors. These two receptor gene families and their roles in the immune response are the topic of this chapter. KIR are found primarily on NK cells but also on NKT cells (a subset of memory T cells with NK receptors), where they may modulate the adaptive immune response by competition with the T-cell receptor for ligand or by modulation of the response depending on which KIR genes are present. Because killing by NK cells is dependent on the strength of signal resulting from the inhibitory-activating receptor competition, pathogenesis can result when either the levels of the signals or the ligands are perturbed. Signaling in NK cells occurs through a variety of receptors, the most well known of which is CD16 (Fc gamma RIII). The signaling pathways are dependent upon the family of NK receptor and upon whether the receptor is activating or inhibitory. The involvement of KIR genes in viral infections and potentially in bone marrow transplantation suggests that KIR typing may have wider application in the future. For this reason, KIR typing by molecular methods is becoming standardized through an ongoing external quality control program.
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- Phospholipase C gamma
HLA class I and KIR gene loci: functionally related gene clusters that exhibit extreme polymorphism. The HLA class I genes map within the MHC at 6p21.3, and the KIR genes map within the leukocyte receptor complex (LRC) at 19q13.4. The KIR gene order is shown for the two distinct KIR haplotypes that have been sequenced in their entirety. Chr., chromosome; ILT, Ig-like transcript; LAIR, leukocyte-associated Ig-like receptor; FCaR, FCα receptor; GPVI, glycoprotein VI.
The basis of KIR nomenclature: domain structure of the KIR molecules. KIR genes express molecules with either two or three extracellular Ig-like domains. The cytoplasmic domains of the inhibitory receptors are long and contain ITIM (I/VXYXXL/V) sequences, whereas a charged amino acid residue, which facilitates interaction with the adaptor molecule DAP12/KARAP, is located in the TM of the short-tailed activating receptors. KIR2DL4 contains signature sequences of both activating and inhibitory receptors. (This figure was adapted from http://web.ncbi.nlm.nih.gov:2441/books/bookres.fcgi/mo no_003/ch140d1.pdf.)
Exon-intron structure of the KIR genes. Exons 1 and 2 correspond to the leader (signal) sequence; exons 3 to 5 correspond to the Ig domains D0, D1, and D2, respectively; exons 6 and 7 correspond to the linker and TM regions, respectively; and exons 8 and 9 correspond to the cytoplasmic domain. All exons are design coded. The genes for type 1 two-domain KIR genes, KIR2DL1, KIR2DL2 and -3, and all 2DS genes, have a genomic organization identical to that of the genes encoding KIR molecules with three Ig domains, but exon 3 (encoding D0) of the genes for two-domain KIR is a pseudoexon (ψ). Exon 3 is also a pseudoexon in the KIR2DP1 gene, which also contains a pseudoexon 4. The genes encoding type 2 two-domain KIR, which include KIR2DL4, KIR2DL5A, and KIR2DL5B, are characterized by the absence of exon 4. (This figure was adapted from http://web.ncbi.nlm.nih. gov:2441/books/bookres.fcgi/mo no_003/ch140d1.pdf.)
KIR haplotypes identified by segregation analysis. Segregation analysis was used to determine the haplotypes shown, many of which are not yet definitive, since it is not always possible to determine gene copy number precisely, even when using family material ( 14 , 19 , 46 , 52 ). KIR2DS4 alleles with the 21-bp deletion are indicated by Δ and those that were not subtyped are marked NS. (This figure was adapted from http://web.ncbi.nlm.nih.gov:2441/books/bookres.fcgi/mono_003/ch140d1.pdf.)