Receptor Types Killer-cell immunoglobulin-like receptor

1 receptor types

1.1 inhibitory receptors
1.2 activating receptors
1.3 expression

receptor types
inhibitory receptors

inhibitory receptors recognize self-mhc class molecules on target self cells, causing activation of signaling pathways stop cytolytic function of nk cells. self-mhc class molecules expressed under normal circumstance. according missing-self hypothesis, inhibitory kir receptors recognize downregulation of mhc class molecules in virally-infected or transformed self cells, leading these receptors stop sending inhibition signal, leads lysis of these unhealthy cells. because natural killer cells target virally infected host cells , tumor cells, inhibitory kir receptors important in facilitating self-tolerance.

kir inhibitory receptors signal through immunoreceptor tyrosine-based inhibitory motif (itim) in cytoplasmic domain. when inhibitory kir receptors bind ligand, itims tyrosine phosphorylated , protein tyrosine phosphatases, including shp-1, recruited. inhibition occurs in activation signaling pathway, through interference of pathway these phosphatases.

activating receptors

activating receptors recognize ligands indicate host cell aberration, including induced-self antigens (which markers of infected self cells , include mica, micb, , ulbp, of related mch class 1 molecules), altered-self antigens (mhc class antigens laden foreign peptide), and/or non-self (pathogen encoded molecules). binding of activating kir receptors these molecules causes activation of signaling pathways cause nk cells lyse virally infected or transformed cells .

activating receptors not have immunoreceptor tyrosine-base inhibition motif (itim) characteristic of inhibitory receptors, , instead contain positively charged lysine or arginine residue in transmembrane domain (with exception of kir2b4) helps bind dap12, adaptor molecule containing negatively charged residue immunoreceptor tyrosine-based activation motifs (itam). activating kir receptors include kir2ds, kir2dl, , kir3ds.

much less known activating receptors compared inhibitory receptors. significant proportion of human population lacks activating kir receptors on surface of nk cells result of truncated variants of kir2ds4 , 2dl4, not expressed on cell surface, in individuals heterozygous kir group haplotype. suggests lack of activating kir receptors not incredibly detrimental, because there other families of activating nk cell surface receptors bind mhc class molecules expressed in individuals phenotype. because little known function of activating kir receptors, however, possible there important function of activating kir receptors of not yet aware.

activating receptors have lower affinity ligands inhibitory receptors. although purpose of difference in affinity unknown, possible cytolysis of target cells occurs preferentially under conditions in expression of stimulating mhc class molecules on target cells high, may occur during viral infection. difference, present in ly49, murine homolog kir, tips balance towards self-tolerance.

expression

activating , inhibitory kir receptors expressed on nk cells in patchy, variegated combinations, leading distinct nk cells. igsf , ctlr superfamily inhibitory receptors expressed on surface of nk cells each expressed on subset of nk cells in such way not classes of inhibitory nk cell receptors expressed on each nk cell, there overlap. creates unique repertories of nk cells, increasing specificity nk cells recognize virally-infected , transformed self-cells. expression of kir receptors determined genetic factors, recent studies have found epigenetic mechanisms play role in kir receptor expression. activating , inhibitory kir receptors recognize same class mhc molecule not expressed same nk cell. pattern of expression beneficial in target cells lack inhibitory mhc molecules express activating mhc molecules extremely sensitive cytolysis.

although initial expression of inhibitory , activating receptors on nk cells appears stochastic, there education process based on mhc class alleles expressed host determines final repertoire of nk receptor expression. process of education not understood. different receptor genes expressed independently of other receptor genes, substantiates idea initial expression of receptors stochastic. receptors not expressed entirely independently of each other, however, supports idea there education process reduces amount of randomness associated receptor expression. further, once nk receptor gene activated in cell, expression maintained many cell generations. appears proportion of nk cells developmentally immature , therefore lack inhibitory receptors, making them hyporesponsive target cells. in human fetal liver, kir , cd49 receptors expressed nk cells, indicating @ least kir receptors present in fetal nk cells, although more studies needed substantiate idea. although induction of nk receptor expression not understood, 1 study found human progenitor cells cultured in vitro cytokines developed nk cells, , many of these cells expressed cd94/nkg2a receptors, ctlr receptor. moreover, there little no kir receptor expression in these cells, additional signals required kir induction.

the balance between effective defense , self-tolerance important functioning of nk cells. thought nk cell self-tolerance regulated educational process of receptor expression described above, although exact mechanism not known. “at least one” hypothesis attractive, though not yet substantiated, hypothesis tries explain way in self-tolerance regulated in education process. hypothesis posits nk cell repertoire regulated @ least 1 inhibitory receptor (either of igsf or ctlr superfamily) present on every nk cell, ensure self-tolerance. effective defense requires opposing pattern of receptor expression. co-expression of many mhc-specific receptors nk cells disfavored, because cells co-express receptors less able attack virally infected or transformed cells have down-regulated or lost 1 mhc molecule compared nk cells co-express receptors lesser degree. minimization of co-expression, therefore, important mounting effective defense maximizing sensitivity of response.