Alleles of the KIR2DL4 receptor and their lack of association with pre-eclampsia

Witt, Campbell S.; Whiteway, Joanna M.; Warren, Hilary S.; Barden, Anne; Rogers, M.; Martin, A.; Beilin, Lawrie J.; Christiansen, Frank

doi:10.1002/1521-4141(200201)32:1<18::aid-immu18>3.0.co;2-7

Cited by 44 publications

(34 citation statements)

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“…First strand cDNA was synthesised from 5 g of total RNA using oligo(dT) [12][13][14][15][16][17][18] primer and 200 U of Superscript II reverse transcriptase (Invitrogen, Carlsbad, CA). The reaction was incubated for 1 h at 42°C and then terminated by heating to 65°C for 15 min.…”

Section: Cdna Productionmentioning

confidence: 79%

“…Exons 6 through 7 were amplified from genomic DNA using primers and method previously described (16). PCR products were sequenced in both directions using M13F and M13R primers and big-dye primer chemistry to determine the transmembrane genotype.…”

Section: Sequencing For Genotypingmentioning

confidence: 99%

“…A linker exon is present following the D2 domain in all transcripts but has been omitted to improve clarity. Superscript 1, Allele name given by Witt et al (16) from which the cDNA was derived. Y/C represents the amino acid polymorphism at aa 53 (D0 domain) of the full length cDNA, including exons 1 and 2, and is due to a G/A substitution at nt 158.…”

Section: Kir2dl4 Is Expressed On Cd56 Bright Peripheral Nk Cells and mentioning

confidence: 99%

“…We have previously reported two genetic variants of the transmembrane exon of the KIR2DL4 gene (16,17). One allele (10A) produces only a single mRNA that appears to code for a classical membrane bound receptor that includes an inhibitory ITIM motif in its cytoplasmic tail.…”

mentioning

confidence: 99%

“…The other mRNA transcript produced by the 9A allele (9A ⌬TM) is more abundant but omits the transmembrane exon, making it unlikely that any translated protein could be expressed on the membrane. Because the 9A and 10A alleles of KIR2DL4 each have a population frequency of 50% (16), this suggests balancing selection and functional importance. Apparent differences in expression and function reported for this receptor could be explained by different groups having studied subjects with different transmembrane genotypes.…”

mentioning

confidence: 99%

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KIR2DL4 (CD158d) Genotype Influences Expression and Function in NK Cells

Goodridge

Witt

Christiansen

et al. 2003

The Journal of Immunology

113

118

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The expression and function of the NK cell receptor KIR2DL4 are controversial. Two common alleles of the transmembrane domain of KIR2DL4 exist. The 10A allele with 10 adenines at the end of the transmembrane exon encodes a full length receptor, whereas the 9A allele has only 9 adenines resulting in a frame shift which in turn generates a stop codon early in the first cytoplasmic exon. The possibility that the 10A and 9A alleles might result in differences in expression and function of KIR2DL4 was explored using mAbs to KIR2DL4. Transfection experiments with cDNA from the 10A and 9A alleles revealed significant membrane expression only with the protein encoded by the 10A allele. Analysis of peripheral blood NK cells demonstrated that only in subjects with at least one 10A allele was cell surface expression of KIR2DL4 detectable, and then only on the minor CD56bright NK cell subset. The major CD56dim NK cell subset did not cell surface express KIR2DL4 but, interestingly, did so after in vitro culture. Functional analysis using cultured NK cells in redirected lysis assays demonstrated that KIR2DL4 is an activating receptor for NK cells with at least one 10A allele. No significant activity was detected for NK cells generated from subjects homozygous for the 9A allele. These data show that genotype influences cell surface expression and function of KIR2DL4 which may account for reported differences in KIR2DL4 expression and function.

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Section: Cdna Productionmentioning

confidence: 79%

Section: Sequencing For Genotypingmentioning

confidence: 99%

Section: Kir2dl4 Is Expressed On Cd56 Bright Peripheral Nk Cells and mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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KIR2DL4 (CD158d) Genotype Influences Expression and Function in NK Cells

Goodridge

Witt

Christiansen

et al. 2003

The Journal of Immunology

113

118

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Three common alleles of KIR2DL4 (CD158d) encode constitutively expressed, inducible and secreted receptors in NK cells

et al. 2006

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Genetic polymorphism of KIR2DL4 results in alleles with either 9 or 10 consecutive adenines in exon 6, which encodes the transmembrane domain. "10A" alleles encode a membrane-expressed receptor that is constitutively expressed on resting CD56bright NK cells and on CD56 dim cells after culture. However, in some individuals with the 10A allele, KIR2DL4 cannot be detected on their resting CD56 bright NK cells. "9A" alleles have been predicted to encode a secreted receptor due to the splicing out of the transmembrane region. In this publication, we show that those individuals with a 10A allele who lack detectable KIR2DL4 on CD56 bright NK cells express a KIR2DL4 receptor in which the D0-domain is excised. This D-D0 receptor cannot be detected by the available anti-KIR2DL4 monoclonal antibodies. In such individuals, KIR2DL4 becomes detectable on cultured NK cells due to up-regulation of the full-length KIR2DL4 transcript. In all individuals with 10A alleles, KIR2DL4 ceases to be expressed at the cell surface 16 days after activation, despite the maintenance of maximal levels of KIR2DL4 mRNA transcription, suggesting the existence of a negative regulator of cell surface expression. Finally, we show that the 9A allele can produce a secreted KIR2DL4 receptor.

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