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Departments of Structural Biology and Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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50% of the population, and is clonally
expressed by NK cells and T lymphocytes (3). Whereas two KIR2DL5 variants (KIR2DL5.1 and .2) were found in the genomic DNA of donor NV, mRNA could only be detected for the KIR2DL5.1 gene and not for KIR2DL5.2 (3). Exons 3 and 4 of KIR2DL5.2, which encode the extracellular Ig-like domains, differ from those of KIR2DL5.1 by only five nucleotide changes, of which three are synonymous and two determine amino acid substitutions in the D2 domain. Introns 2 and 3 of both variants were found to differ by a single nucleotide replacement (our unpublished observation), all their splicing sites conforming to the AG/GT rule. Since the sequenced regions of KIR2DL5.2 harbored no obvious structural defects, we could not ascertain whether it represents a null version of the KIR2DL5 gene or whether its lack of expression in the donor studied was due to some form of negative regulation.
To establish whether expression or its lack correlate with particular structural variants of the KIR2DL5 gene and to assess further its polymorphism, we have studied the expression and nucleotide sequence of this gene in different donors. We have also investigated the organization of the KIR2DL5 gene and verified the structural integrity of the exons and introns of KIR2DL5.2 by determination of the complete nucleotide sequence. Finally, we have characterized the promoter regions of expressed and nonexpressed KIR2DL5 variants in different donors to identify the elements that regulate transcription of this gene.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Genomic DNA from seven donors was analyzed by PCR with sequence-specific primers (PCR-SSP), using primers that recognize single nucleotide differences between variants .1 and .2 of the KIR2DL5 gene. Of the seven donors, four (WCS, WCJ, CC, and VH) were of African-American origin, two (RR and SK) were Asian Indians, and one (BS) was Chinese. Donors WCS and CC were the parents of WCJ; VH was the mother of donor CC. PCR-SSP typing of KIR2DL5.1 and .2 was performed using primer pairs F153/Rc939 and Fa139/Ra964, respectively, as previously described (3). F153/Rc939 recognize, in addition to KIRDL5.1, the new variants described in this article, KIR2DL5.3 and .4.
RNA isolated from PBMC of all seven donors was submitted to RT-PCR using primers FLcon63 and LRg1769, which amplify the entire coding region of KIR2DL5 (3). PCR products were obtained from five donors (BS, SK, WCS, WCJ, and VH), and their nucleotide sequences were determined after molecular cloning. No amplification products were obtained from cDNA of donors RR and CC.
Exons 2–4 of KIR2DL5 were amplified from genomic DNA of donors CC and VH by PCR with primers Fcon113 and Ra964 (3). The PCR products were cloned and the nucleotide sequences of exons 2, 3, and 4 were determined.
In all cloning experiments, PCR products were inserted into the pCR2.1-TOPO or pCR4-TOPO plasmid vectors (Invitrogen, San Diego, CA). Plasmids were isolated from individual bacterial clones using the Qiaprep Spin miniprep kit (Qiagen, Chatsworth, CA). Nucleotide sequences were determined using dye-labeled deoxy-terminators and either 373A or 377 automated DNA sequencers (PE Applied Biosystems, Foster City, CA).
Genomic DNA cloning of KIR2DL5.1 and KIR2DL5.2
To amplify the complete KIR2DL5.1 and KIR2DL5.2 genes of donor NV, long-range PCR was performed on his genomic DNA using three different primer combinations. First, we used the FLcon63 and LRg1769 primers, which recognize the 5' and 3' untranslated regions (UTR) of KIR2DL5. Clones corresponding to both KIR2DL5.1 and .2 were obtained from this PCR product, as assessed by partial nucleotide sequencing, which also revealed that these variants have a single nucleotide polymorphism in exon 1. Based on this polymorphism, we designed new forward primers recognizing exon 1 of KIR2DL5.1 and KIR2DL5.2: LFa80 (5'-GCAGCACCATGTCGCTCATGGTCA-3') and LFcon80 (5'-GCAGCACCATGTCGCTCATGGTCG-3'), respectively. LFa80 and LFcon80 were combined with LRg1769 to amplify separately the two variants of KIR2DL5.
In all PCR experiments, 200 ng of DNA were amplified in 25 µl of
high-salt PCR buffer containing 0.5 µl of TaqPlus Long-DNA polymerase
(Stratagene, La Jolla, CA) and 10 pmol of each primer. The PCR profile
was 5 min of denaturation at 95°C and 30 cycles of 40 s at
94°C, 50 s at 68°C, and 20 min at 72°C, followed by a 5-min
extension period at 72°C. PCR products with lengths of 9 kb were
obtained and they were cloned as above. One clone for each
KIR2DL5 variant was selected among those derived from the
LFcon63/LRg1769 amplification; and two additional clones for each of
the variants were selected from the variant-specific amplifications.
Complete nucleotide sequences were determined for both DNA strands of
all six clones.
Molecular cloning of the promoters of four KIR2DL5 variants
Two 2.5-µg samples of genomic DNA of donor NV were digested separately with the restriction endonucleases DraI and ScaI according to the recommendations of the manufacturer (Genome Walker kit; Clontech, Palo Alto, CA). Digests (DraI-DNA and ScaI-DNA, hereafter) were purified by extraction with phenol and chloroform, precipitated with ethanol and 3 M sodium acetate (pH 4.96), and resuspended in 20 µl of TE buffer. One-fifth of each digest was ligated to the GenomeWalker adaptor during 16 h at 16°C. The ligation reaction was stopped by a 5-min incubation at 72°C and diluted with 9 vol of TE (10 mM Tris-HCl (pH 8.0) and 1 mM Na2 EDTA). One-eightieth of each ligation was PCR-amplified using the Adaptor Primer ACP1 (Clontech) and the reverse oligonucleotide primer LRa302 (5'-CAGGGGTCACAGGGCCCATGAGGAT-3'), specific for exon 3 of KIR2DL5. PCR was done in 25 µl of Advantage 2 PCR buffer containing 0.5 µl of Advantage 2 polymerase mix (Clontech), 0.5 µl of ACP1, and 5 pmol of LRa302. The PCR profile was: 2 min denaturation at 95°C; 5 cycles of 2 s at 94°C and 10 min at 72°C; and 32 cycles of 2 s at 94°C and 10 min at 70°C.
One microliter of each PCR product was diluted with 49 µl of TE and 1 µl of each dilution was used as a template for PCR with the nested primers ACP2 (Clontech) and LRt207 (5'-GTAAACCCAAGACGAGAGCGACACA-3'). PCR conditions were: 2 min denaturation at 95°C; 5 cycles of 2 s at 94°C and 10 min at 72°C; and 20 cycles of 2 s at 94°C and 10 min at 70°C. The PCR products were cloned and their nucleotide sequences were determined.
Clones obtained from ScaI-DNA contained a longer segment of sequence (2793 bp) upstream of the KIR2DL5 coding region than clones derived from DraI-DNA (474/532 bp). However, whereas both KIR2DL5.1 and KIR2DL5.2 were represented among DraI-DNA clones, all ScaI-DNA clones corresponded to the KIR2DL5.2 variant and none was obtained for KIR2DL5.1. The 5'-most 763 bp of ScaI-DNA clones carried sequences corresponding to the 3'-most exon of the KIR2DL2 gene.
To isolate the entire promoter region of KIR2DL5.1, we took advantage of the close juxtaposition of KIR genes. Unmodified genomic DNA of donor NV was amplified by long-range PCR with a sense primer recognizing the last exon of all KIR (LF1450: 5'-CTTCTAGGGAGACAACAGCCCTG-3') in combination with an antisense primer specific for exon 3 of KIR2DL5.1 (LRcon364: 5'-TGCTGACCACTCAATGGGGGAGCGT-3'). One hundred nanograms of DNA was amplified with 5 pmol of each LF1450 and LRcon364 in the following PCR conditions: 2 min denaturation at 95°C; 10 cycles of 2 s at 94°C and 10 min at 72°C; and 20 cycles of 2 s at 94°C and 10 min at 70°C. Similarly, the promoter region of KIR2DL5 was isolated from genomic DNA of donors VH, BS, SK, RR, WCS, and CC using LF1450 and LRa302 primers in the same conditions.
Sequence analysis
Nucleotide sequences were aligned and compared using AutoAssembler (PE Applied Biosystems) and the Wisconsin Package Version 10.0 (Genetics Computer Group, Madison, WI). Analysis of potential regulatory elements in the promoter region of KIR2DL5 variants was performed using free test analyses of MatInspector Professional (Genomatix, http://genomatix.gsf.de/free services/) (9) and the TRANSFAC database (10).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Previously, we identified two variants of KIR2DL5 in
the genomic DNA of one individual, donor NV (3). Of the
two variants, KIR2DL5.1 was transcribed in NK cells and T
lymphocytes, whereas KIR2DL5.2 was not. To investigate
variation in KIR2DL5 further, we analyzed genomic DNA of an
additional seven donors using PCR-SSP and oligonucleotide primers that
discriminate sequence polymorphisms in exons 3 and 4 of
KIR2DL5.1 and KIR2DL5.2. Of the seven donors
analyzed (Table I
), one typed for both
variants, one typed only for KIR2DL5.2, and five donors
typed for just KIR2DL5.1. Subsequent analysis (see below)
showed that three of the latter five donors actually have novel
variants of KIR2DL5.
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).
At all three positions, KIR2DL5.3 shows identity with other
KIR genes, whereas KIR2DL5.1 has a unique substitution. Although
genomic DNA from donor VH typed positively for both
KIR2DL5.1 and .2, only cDNA clones for
KIR2DL5.1 were obtained.
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). When the oligonucleotide primers
that amplified the genomic fragment of KIR2DL5.4 were tested
against cDNA from donor CC, no product was obtained. This result
confirmed that KIR2DL5.4 is not expressed and ruled out the
possibility that lack of amplification in the first RT-PCR experiments
was due to polymorphism in one or both of the priming sites. KIR2DL5.1 and KIR2DL5.2 have similar open reading frames
To search for structural features that might account for the inability of KIR2DL5.2 to be expressed and to establish the structure of the KIR2DL5 gene, the nucleotide sequences for all of the exons and introns of the KIR2DL5.1 and KIR2DL5.2 genes were determined and compared. Clones containing all of the exons were obtained from genomic DNA by a long-range PCR using primers that recognized the 5' and 3' UTR of KIR2DL5. For each variant, complete sequences were determined for both strands of three clones derived from two different PCR amplifications, a strategy designed to eliminate the effect of polymerase errors during PCR.
The KIR2DL5 gene contains eight exons that are organized
similar to those of the KIR2DL4 gene (11). The
KIR2DL5 exons extend over 9.3 kb of DNA, which is about
1.5 kb shorter than for KIR2DL4, due mainly to differences
in the lengths of introns 1, 4, and 5 (Table III). The overall organization of the
KIR2DL5.1 and .2 genes is the same (Table III).
In both variants, the exons make an open reading frame of 1128 nt and
they are flanked by splicing sites that conform to the consensus
motifs. Within the exons, there is a total of seven nucleotide
substitutions, none of which are predicted to have an effect on gene
expression (Tables II and III). Within the introns,
KIR2DL5.1 and .2 differ by 32 nt substitutions
and 4 insertions/deletions (Table III), one of which occurs in a tandem
repeat of a 19- or 20-nucleotide unit that comprises most of intron 1
(data not shown).
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As the exons and introns revealed no feature that could account
for the nonexpression of KIR2DL5.2, we turned to compare the
promoter regions of KIR2DL5 variants. Genomic DNA from donor
NV, who has both KIR2DL5.1 and .2, was digested
with either DraI or ScaI restriction enzymes that
cut neither KIR2DL5 variant in the DNA segment encompassing
exons 1–4. An artificial adaptor sequence was ligated to the
blunt-ended DNA fragments produced by the digest. Nested PCR was then
performed using antisense primers specific for exon 3 of
KIR2DL5 and primers targeted at the adaptor sequence. PCR
products of 2 and 4 kb were obtained from the DraI-
and ScaI-digested DNA, respectively. These fragments were
cloned and sequenced.
Clones corresponding to KIR2DL5.1 and .2 were
obtained from the DraI digest. They contained 500 bp of
DNA that was derived from the region upstream of the putative start
codon. In contrast, only clones corresponding to KIR2DL5.2
were obtained from the ScaI digest. These clones contained
2793 bp of DNA from the region upstream of the putative start codon, of
which the 5'-most 763 bp were identified as the 3'-most exon of the
KIR2DL2 gene. Thus, the end of the KIR2DL2 gene
and the start codon of KIR2DL5.2 are separated by only
2030 bp.
By taking advantage of the close juxtaposition of KIR genes (Ref.
4 and this article), we were able to isolate clones that
encompassed the entire noncoding upstream region of the
KIR2DL5.1 gene. PCR was performed using an antisense primer
specific for exon 3 of KIR2DL5.1 in combination with a sense
primer recognizing the last exon of all KIR. The product of this PCR
contained exon 9 of KIR3DS1 at its 5' end and exons 1–3 of
KIR2DL5.1 at its 3' end. Determination of the nucleotide
sequence of this product showed that the region 5' of the start codon
is similar in KIR2DL5.1 and .2 despite their
being next to other different KIR genes (KIR3DS1 and
KIR2DL2, respectively). In this 2-kb region,
KIR2DL5.1 and .2 differ by 32 single nucleotide
replacements and a 58-nt insertion in KIR2DL5.2 (Fig. 1). This insertion is the duplication of
a contiguous sequence from which it differs by three point
substitutions. A 255-bp-long inverted Alu-Sx repeat is situated in both
KIR2DL5.1 and .2 between nucleotides -707 and
-961 from the start codon (data not shown).
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1.2-kb DNA segment upstream of the
initiation codon was determined. This allowed the promoters of all four
KIR2DL5 variants to be compared, as well as several
independently isolated KIR2DL5.1 and .2 variants.
In all isolates of KIR2DL5.1, we found KIR3DS1 to
be the gene upstream of KIR2DL5.1, and in all isolates of
KIR2DL5.2 and .4, we found the upstream gene to
be KIR2DL2. The KIR gene sequence found upstream of
KIR2DL5.3 was not a complete match with any of the known KIR
genes, being closest to the 3'-most exon of KIR2DL2 (data
not shown).
The promoter sequences were identical in the KIR2DL5.1 genes
obtained from four donors (NV, VH, BS, and SK). Similarly, the
KIR2DL5.2 promoter sequences from three donors (NV, RR, and
VH) were identical and they were also identical to the
KIR2DL5.4 promoter. A promoter of a different sequence was
found in KIR2DL5.3, which differs from those of
KIR2DL5.1 and .2 by 28 and 32 substitutions,
respectively. It contains some unique substitutions, in addition to
elements in common with each of the other two promoters (Fig. 1).
Comparison of the promoter sequences of the expressed and nonexpressed
KIR2DL5 variants was made (Fig. 1). The 58-bp insertion,
which was first found in KIR2DL5.2, is unlikely to be
responsible for the lack of expression because this insertion is also
present in the expressed variant KIR2DL5.3. More likely
candidates are 11 changes that are specific to the nonexpressed
variants. A search for regulatory elements of transcription was
performed in the promoters of KIR2DL5 variants, and several
transcription factor binding sites that are present in the expressed
KIR2DL5 variants and absent in the nonexpressed variants
were found (Fig. 1). Of these, only AML1 is known to function in
hematopoietic cells (12). In the T cell lineage, AML1
cooperates with the transcription factor erythroblastosis virus
oncogene homologue 1 (Ets-1) in the activation of the TCR-
chain
enhancer (13). Indeed, two potential binding sites for
Ets-1 were found flanking the AML1-binding motif (14)
present in positions -95 to -100 of KIR2DL5.1 and .3 and
which is mutated from TGTGGT to TGTAGT in the
nontranscribed variants KIR2DL5.2 and .4
(Fig. 1).
Common to all four KIR2DL5 variants are binding sites for transcription factors that are expressed ubiquitously in all cells or in hematopoietic lineage cells (15, 16, 17): AP-1, Sp1, Oct-1, GATA, NFAT-1, Ikaros, STATs, Ets-1, and AML1 (data not shown). No TATA box was found in the vicinity of the transcription start site, as assessed by rapid amplification of cDNA ends in KIR2DL5.1 (3). Absence of a TATA box is associated with variability in the site in which transcription is initiated, as has been recently shown for the murine NK cell receptor 2B4 (18).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The expression of each KIR2DL5 variant, or its lack, are
consistently reproduced in different individuals (Table II). This
argues against the possibility of KIR2DL5.2 nonexpression
being determined by some sort of regulation that could vary in
different donors. In particular, lack of KIR2DL5.2 mRNA in
one donor (RR) in whom this variant was found in the absence of
KIR2DL5.1 excluded monoallelic expression as the cause of
KIR2DL5.2 being a silent gene. Two additional variants of
the gene, one expressed (KIR2DL5.3) and one nonexpressed
(KIR2DL5.4), were found in this study. Altogether, the
results of this survey are consistent with expression or its lack being
constitutive features of certain variants of the
KIR2DL5 gene.
Genomic DNA cloning of KIR2DL5.1 and KIR2DL5.2
after long-range PCR provided the complete exon and intron sequences of
both KIR gene variants. However, we found no structural abnormalities
in KIR2DL5.2 that might explain its lack of expression or
suggest that KIR2DL5.2 is a pseudogene, all its differences
from KIR2DL5.1 being minor in nature. In contrast, analysis
of the KIR2DL5 promoter revealed a high level of sequence
polymorphism that is likely relevant for expression. Whereas the
promoters of each of the expressed variants have distinctive sequences,
the two nontranscribed versions of the gene have the identical
promoter. The identity of KIR2DL5.2 and .4
promoter sequences contrasts with the coding regions of these variants
being among the most divergent within the KIR2DL5 group
(Table II) and supports their lack of expression being determined by
shared features in their promoters.
One of the changes that distinguish the promoters of expressed and nonexpressed KIR2DL5 variants takes place in a putative binding site for the transcription factor AML1, also known as CBP or PEBP2 (14). AML1 controls the expression of several genes that are essential for the development and function of hematopoietic cells, including those encoding Ag receptors of T and B lymphocytes and granzyme B (12, 20, 21). This protease is present in the lytic granules of NK cells (22), an indication of AML1 activity in these cells. Also, cooperation of AML1 with Ets-1 (13, 23) and the presence of potential binding sites for the latter transcription factor in the proximal promoter of KIR2DL5 make it likely that AML1 and Ets-1 participate in the regulation of KIR2DL5 expression. The observed mutation of an AML1 binding site in the promoters of KIR2DL5.2 and KIR2DL5.4 might thus be responsible for their lack of transcription, an issue that will be illuminated by functional analysis of KIR2DL5 promoters. However, we cannot exclude that expression of KIR2DL5 could be affected by unknown polymorphisms at more distant regulatory elements.
Comparing the sequences of KIR2DL5 variants also reveals
aspects that are intriguing from the evolutionary aspect. Because
KIR2DL5.2 is not expressed, non-sense mutations and other
aberrations could have accumulated in this gene due to the lack of
selective pressure. However, no such abnormalities were found, which
indicates a recent inactivation of KIR2DL5.2. In addition,
the similarity in the coding regions and introns of KIR2DL5
variants (0.42% differences, Table III) is consistent with their
recent separation from a common ancestor. In contrast, the promoters of
expressed and nonexpressed variants differ by 1.61–2.46% (Fig. 1).
This 3.8- to 5.8-fold higher number of differences could mean that the
promoters of the different variants have accumulated mutations at a
higher rate than structural parts of the gene. Alternatively, stretches
of new sequence motifs could have been introduced in their promoters by
recombination with other KIR genes. In the case of
KIR2DL5.1, its location downstream of a KIR gene different
from other KIR2DL5 variants indicates that recombination
indeed affected its upstream region at some moment of evolution.
Before the description of KIR2DL5 and KIRC1/KIR44 (3, 24), all KIR genes had been shown to be expressed in every individual in whom they are present (8). Variability in the expression of KIR2DL5 is an exception to this rule and adds to the variation in the number and combination of KIR genes present in the genome of different humans (8). Also, nonexpression of structurally normal KIR2DL5 variants parallels the lack of transcription of KIRC1/KIR44, a gene that also contains an open reading frame similar to that of other KIR (24). Since mRNA of KIRC1/KIR44 has only been sought in seven individuals (3, 24), the variation observed in transcription of KIR2DL5 prompts further analysis of the expression of KIRC1/KIR44 in a wider population sample.
KIR2DL5 is the first KIR gene whose promoter has been structurally characterized. Comparison of its sequence with those of other KIR genes should shed light on the three types of KIR gene expression observed in NK cells: clonal distribution of certain KIR2DL5 variants and most KIR genes (3, 7), lack of transcription of other KIR2DL5 variants and KIRC1/KIR44 (3, 24), and constitutive transcription of KIR2DL4 (5, 7). In addition, our study opens a way to the functional analysis of the KIR2DL5 promoter, which should illustrate how the expression of its variants is controlled. Since KIR can modulate the function of NK cells and subsets of T lymphocytes, the issue of how KIR gene expression is regulated is relevant for better understanding of both natural and adaptive immunity and tolerance.
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Acknowledgments |
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Footnotes |
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2 The sequences reported in this article have been submitted to GenBank under accession numbers AF217485 (KIR2DL5.1 gene and promoter), AF217486 (KIR2DL5.2 gene and promoter), AF217487 (KIR2DL5.3 cDNA), AF260137 (KIR2DL5.3 promoter region), and AF260138–AF260141 (KIR2DL5.4 promoter region and exons 1–4).
3 Current address: Servicio de Inmunología, H.U. Clínica Puerta de Hierro, San Martín de Porres 4, 28035 Madrid, Spain.
4 Address correspondence and reprint requests to Dr. Peter Parham, Departments of Structural Biology and Microbiology and Immunology, Stanford University School of Medicine, Sherman Fairchild Building, Stanford, CA 94305.
5 Abbreviations used in this paper: KIR, killer-cell Ig-like receptor; UTR, untranslated region; SSP, sequence-specific primer; AML1, acute myeloid leukemia gene 1; Ets-1, erythroblastosis virus oncogene homologue 1.
Received for publication June 23, 2000. Accepted for publication September 8, 2000.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-chain core promoter. Mol. Cell. Biol. 17:4220.[Abstract]
2) cooperates with B cell-specific activating protein (BSAP/PAX5) in activation of the B cell-specific BLK gene promoter. J. Biol. Chem. 274:24671.This article has been cited by other articles:
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  A. Iannello, O. Debbeche, S. Samarani, and A. Ahmad Antiviral NK cell responses in HIV infection: I. NK cell receptor genes as determinants of HIV resistance and progression to AIDS J. Leukoc. Biol., July 1, 2008; 84(1): 1 - 26. [Abstract] [Full Text] [PDF]
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 E. Estefania, R. Flores, N. Gomez-Lozano, H. Aguilar, M. Lopez-Botet, and C. Vilches Human KIR2DL5 Is an Inhibitory Receptor Expressed on the Surface of NK and T Lymphocyte Subsets J. Immunol., April 1, 2007; 178(7): 4402 - 4410. [Abstract] [Full Text] [PDF]
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C. J. VandenBussche, S. Dakshanamurthy, P. E. Posch, and C. K. Hurley A Single Polymorphism Disrupts the Killer Ig-Like Receptor 2DL2/2DL3 D1 Domain J. Immunol., October 15, 2006; 177(8): 5347 - 5357. [Abstract] [Full Text] [PDF]
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 M. Yawata, N. Yawata, M. Draghi, A.-M. Little, F. Partheniou, and P. Parham Roles for HLA and KIR polymorphisms in natural killer cell repertoire selection and modulation of effector function J. Exp. Med., March 20, 2006; 203(3): 633 - 645. [Abstract] [Full Text] [PDF]
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S.-i. Yusa, T. L. Catina, and K. S. Campbell KIR2DL5 Can Inhibit Human NK Cell Activation Via Recruitment of Src Homology Region 2-Containing Protein Tyrosine Phosphatase-2 (SHP-2) J. Immunol., June 15, 2004; 172(12): 7385 - 7392. [Abstract] [Full Text] [PDF]
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M. P. Martin, A. Bashirova, J. Traherne, J. Trowsdale, and M. Carrington Cutting Edge: Expansion of the KIR Locus by Unequal Crossing Over J. Immunol., September 1, 2003; 171(5): 2192 - 2195. [Abstract] [Full Text] [PDF]
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C. A. Stewart, J. van Bergen, and J. Trowsdale Different and Divergent Regulation of the KIR2DL4 and KIR3DL1 Promoters J. Immunol., June 15, 2003; 170(12): 6073 - 6081. [Abstract] [Full Text] [PDF]
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K. C. Hsu, X.-R. Liu, A. Selvakumar, E. Mickelson, R. J. O'Reilly, and B. Dupont Killer Ig-Like Receptor Haplotype Analysis by Gene Content: Evidence for Genomic Diversity with a Minimum of Six Basic Framework Haplotypes, Each with Multiple Subsets J. Immunol., November 1, 2002; 169(9): 5118 - 5129. [Abstract] [Full Text] [PDF]
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S. Santourlidis, H.-I. Trompeter, S. Weinhold, B. Eisermann, K. L. Meyer, P. Wernet, and M. Uhrberg Crucial Role of DNA Methylation in Determination of Clonally Distributed Killer Cell Ig-like Receptor Expression Patterns in NK Cells J. Immunol., October 15, 2002; 169(8): 4253 - 4261. [Abstract] [Full Text] [PDF]
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C. M. Gardiner, L. A. Guethlein, H. G. Shilling, M. Pando, W. H. Carr, R. Rajalingam, C. Vilches, and P. Parham Different NK Cell Surface Phenotypes Defined by the DX9 Antibody Are Due to KIR3DL1 Gene Polymorphism J. Immunol., March 1, 2001; 166(5): 2992 - 3001. [Abstract] [Full Text] [PDF]
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