| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Division of Viral Pathogenesis, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Extensive characterization of cDNA from humans has revealed 13 forms of KIR molecules (1, 2, 9, 14, 15). The polymorphism, genomic organization, and alternative mRNA splicing of these molecules have been characterized. The number of KIR genes varies among individuals, and additional KIR genotypic diversity occurs due to allelic polymorphism (16, 17, 18, 19). However, the sequence differences between these various alleles is minimal, usually fewer than five amino acid changes. KIR3D molecules and the KIR2D molecule with the D1-D2 Ig domains have nine exons, and KIR2D molecules with D0-D2 domains have eight exons (17, 20, 21, 22). Variations in mRNA splicing have been described for several human KIR molecules. Complete deletion of the exons encoding the Ig domains, the stem domain, and the transmembrane domain, as well as the first exon of the cytoplasmic domain have been reported (9, 14, 17, 23). In addition, deletions of only portions of the Ig domains have been detected (23, 24).
No KIR homologues have been identified in rodents, and the only species other than humans in which these molecules have been characterized is the chimpanzee (25). This recent analysis of cDNA from chimpanzees identified 10 forms of KIR molecules (Pt-KIR), four of which have at least 95% nucleotide sequence identity to their human homologues. The other six Pt-KIR molecules, although more divergent, have the same structural configuration as a human KIR molecule. Because humans and chimpanzees are very close phylogenetically, it is not surprising that all of the Pt-KIR molecules are similar to the human KIR molecules. Thus, we do not have a complete understanding of the evolutionary history of these molecules. In the present study, we have characterized the KIR molecules in rhesus monkeys. Surprisingly, we found two novel KIR molecules, as well as considerable diversity of the KIR3DL molecules in this species. The detection of this diversity of KIR molecules in rhesus monkeys indicates that extensive evolution has occurred in this receptor family in primates.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
EDTA-anticoagulated peripheral blood samples were obtained from five unrelated rhesus monkeys (Macaca mulatta). These animals were maintained in accordance with the guidelines of the Committee on Animals for the Harvard Medical School and the "Guide for the Care and Use of Laboratory Animals" (National Research Council, National Academic Press, Washington, DC, 1996).
RNA extraction and reverse transcription
PBMC were isolated from whole blood by centrifugation over Ficoll-Hypaque (Ficopaque; Pharmacia, Piscataway, NJ). Total RNA was extracted from 2–5 x 106 PBMC by using the RNeasy miniprep kit with a DNase treatment step (Qiagen, Chatsworth, CA). First-strand cDNA was generated by using avian myeloblastosis virus reverse transcriptase and an oligo(dT) primer (Promega, Madison, WI).
PCR amplification
Rhesus monkey KIR sequences were amplified by using the sense primer Ig3Up and the antisense primer Ig3Down, which are based on the human KIR molecules (26). Amplification of 2 µl of cDNA was performed in 50-µl reactions with 1x PCR Buffer II, 2 mM MgCl2, 200 µM of each of the four dNTPs, 50 pmol of each primer, and 2.5 U of AmpliTaq Gold (Perkin-Elmer, Foster City, CA). PCR cycling conditions were as follows: initial denaturation and activation of AmpliTaq Gold for 10 min at 94°C, followed by 30–35 cycles of denaturation at 94°C for 30s, annealing at 60°C for 30s, extension at 72°C for 90s, and a final extension at 72°C for 10 min.
KIR molecules homologous to the human KIR3DL (Mm-KIR3DL) and KIR2DL4 (Mm-KIR2DL4.1 and Mm-KIR2DL4.2) molecules, as well as splice variants of these molecules, were amplified from the cDNA of rhesus monkeys by using the Ig3Up-Ig3Down primer combination. In addition, the novel rhesus monkey KIR molecule Mm-KIR3DH was amplified from one animal (577) by using these primers.
Additional KIR sequences were amplified from the cDNA of two rhesus monkeys (223 and 227) by using the human KIR-specific primers, sense primer F23, and the antisense primer R1441 (1). PCR conditions were the same as described above, but the annealing temperature was 57°C. Extensive analysis of the PCR products amplified by this primer combination from the cDNA of monkey 223 identified Mm-KIR3DL molecules, splice variants of Mm-KIR3DL, Mm-KIR2DL5.1, and the novel rhesus monkey KIR molecule Mm-KIR1D and its splice variants. A second Mm-KIR2DL5 sequence was identified in the F23-R1441 PCR products by using cDNA from monkey 227 as template.
The novel rhesus monkey KIR molecule Mm-KIR3DH and its splice variants were amplified from the cDNA of two rhesus monkeys (223 and 577) by using the Mm-KIR3DH-specific reverse primer (5'-CTGGGCTGGAGACAACGA-3') in conjunction with Ig3Up. PCR conditions were the same as described above, but the annealing temperature was 55°C.
3' Rapid amplification of cDNA ends (RACE)
For 3' RACE, first-strand cDNA was synthesized with Superscript II reverse transcriptase by using the adapter primer (Life Technologies, Rockville, MD). PCR then was performed with Ig3Up and the abridged universal amplification primer (Life Technologies). Amplification of 2 µl of cDNA was performed in 50-µl reactions with 1x PCR Buffer II, 2.5 mM MgCl2, 200 µM of each of the four dNTPs, 10 µM of each primer, and 2.5 U of AmpliTaq Gold (Perkin-Elmer). PCR cycling conditions were as described above, but the annealing temperature was 55°C. 3' RACE with Ig3Up and abridged universal amplification primers amplified Mm-KIR3DL, Mm-KIR3DH, and Mm-KIR2DL4.1 molecules.
Cloning and sequencing
PCR products were analyzed on a 1% agarose gel and purified from the gel by using the Qiaex II gel extraction kit (Qiagen). Purified PCR products were cloned into the p-GEM-T Easy vector (Promega). Plasmids were isolated from bacterial clones with the Qiaprep spin miniprep kit (Qiagen). These plasmids then were sequenced by using the ABI PRISM Dye Terminator Cycle Sequencing Ready Reaction kit and a 377 automated DNA sequencer (Applied Biosystems, Foster City, CA).
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
We identified cDNA sequences that encode a family of rhesus monkey
KIR molecules with three Ig domains and long cytoplasmic tails.
Consistent with the nomenclature used to describe the homologous human
KIR molecules, we refer to these molecules as Mm-KIR3DL with the prefix
Mm denoting M. mulatta. Members of this family of rhesus
monkey KIR3DL molecules (Mm-KIR3DL) were classified into distinct types
based on predicted amino acid sequence homology. Members that differed
by >2% were considered separate types. Although only two KIR3DL
molecules have been defined in humans, eleven distinct molecules were
identified by this criterion in PBMC of five unrelated rhesus monkeys
(Figs. 1
and 3). The amino acid
differences among these eleven types are scattered throughout the
linear sequences of the molecules and do not cluster in any distinct
regions. However, there are certain amino acid changes that are
consistently seen in a number of these molecules. For example,
Mm-KIR3DL1 through Mm-KIR3DL4 share a number of amino acid changes
throughout the Ig domains but are divergent in their cytoplasmic
domains (Fig. 1). Despite the sequence variation among the Mm-KIR3DL
molecules, the two cysteines important for the Ig fold are conserved in
all three Ig domains in all of these molecules. Also, like their human
homologues, the cytoplasmic tails of the Mm-KIR3DL molecules contain
two ITIMs.
|
|
and 2). In addition, the cytoplasmic tails of
Mm-KIR3DL molecules are the same length as the cytoplasmic tail of
human KIR3DL1. Therefore, these rhesus monkey molecules most closely
resemble human KIR3DL1. Despite the similarity to the human KIR3DL
forms, the Mm-KIR3DL molecules are distinguished from human KIR3DL1 and
KIR3DL2 molecules by a 3-aa insertion in the D0 domain and a 1-aa
deletion in the transmembrane domain (Fig. 2).
|
). In no
rhesus monkey were fewer than three forms of Mm-KIR3DL detected,
indicating that multiple Mm-KIR3DL gene loci exist in this species. Alternatively spliced forms of Mm-KIR3DL
Seven alternatively spliced forms of the Mm-KIR3DL molecules were
identified (Fig. 4). Splice variants
Mm-KIR3DLsv1, Mm-KIR3DLsv5, and Mm-KIR3DLsv6 have deletions that follow
exon boundaries and therefore are likely to occur as a result of exon
skipping. The Mm-KIR3DLsv1 and Mm-KIR3DLsv5 variants lack an entire Ig
domain and would form KIR molecules with only two Ig domains. The D0
domain deletion seen in Mm-KIR3DLsv1 has been reported previously for
the human KIR3DL1 molecule (23). The combination of D0 and
D2 domain deletions seen in Mm-KIR3DLsv6 would result in a KIR molecule
with only a single Ig domain. Splice variants were also detected with
only a portion of an Ig domain deleted. These variants (Mm-KIR3DLsv2,
Mm-KIR3DLsv3, and Mm-KIR3DLsv4) remain in the same reading frame and
have at least two complete Ig domains. Deletions of only a portion of
an Ig domain have been described previously for the human KIR molecules
(24). A splice variant of the human KIR2DL3 molecule was
identified previously with the same 50-aa deletion of the D2 domain as
Mm-KIR3DLsv4. However, the deletions of Mm-KIR3DLsv2 and Mm-KIR3DLsv3
have not been reported previously for human KIR molecules. All variants
resulting from these in-frame deletions have normal stem,
transmembrane, and cytoplasmic domains. However, a deletion of D2 that
resulted in a shift in the reading frame by one nucleotide was also
identified (Mm-KIR3DLsv7). This frame-shifted molecule terminates early
without an identifiable transmembrane or cytoplasmic domain. Because
the nucleotide sequences of all of the splice variants identified in an
individual monkey are in every case identical with a Mm-KIR3DL sequence
detected in that monkey, these internally deleted cDNAs most likely
represent splice variants rather than distinct genes.
|
We identified cDNA sequences that encode molecules with 84% amino
acid identity to human KIR2DL4 that have only the D0 and D2 Ig domains
and long cytoplasmic tails. These molecules also contain an arginine in
their transmembrane domains. Because of these characteristic features,
these molecules are likely to be rhesus monkey homologues of KIR2DL4
and therefore were designated Mm-KIR2DL4 (Fig. 5). Despite their obvious homology to
human KIR2DL4, these molecules are distinguished by the two ITIMs in
their cytoplasmic tails. Both the human and chimpanzee KIR2DL4
molecules have only one ITIM in their cytoplasmic domains (15, 25). The human KIR2DL4 has an ITIM at amino acids 298–303, the
chimpanzee KIR2DL4 has an ITIM at amino acids 328–333, and the rhesus
monkey KIR2DL4 molecules have ITIMs at both positions. Therefore, the
positions of the two ITIMs in the Mm-KIR2DL4 molecules are the same as
those of the ITIMs found individually in their human and chimpanzee
homologues (Fig. 5).
|
In addition to subtype variation, allelic polymorphism was identified for both types of Mm-KIR2DL4 molecules. Every monkey characterized expressed mRNA for at least one subtype of the Mm-KIR2DL4 molecule. One monkey had molecules of both subtypes, and one monkey had two alleles of Mm-KIR2DL4.2 but no Mm-KIR2DL4.1. The remaining three animals expressed mRNA for a single allele of either subtype. Finally, a splice variant of an allele of Mm-KIR2DL4.2 lacking the D0 domain was detected (data not shown). Although alternatively spliced forms of the human KIR2DL4 molecule have been described previously, none involved an Ig domain (17).
Mm-KIR2DL5
We also identified cDNA sequences that encode a second KIR
molecule with only D0 and D2 Ig domains. This molecule has 
80%
amino acid identity to the human KIR2DL5 molecule. Although this rhesus
monkey molecule also has similarities to human KIR2DL4 (79% amino acid
identity), it lacks the arginine in the transmembrane domain that is
characteristic of KIR2DL4 and contains two ITIM motifs in the
cytoplasmic tail (Fig. 6). Therefore, we
refer to this molecule as Mm-KIR2DL5. Distinct sequences of Mm-KIR2DL5
with >2% amino acid divergence were identified from two rhesus
monkeys. Therefore, these molecules were designated Mm-KIR2DL5.1 and
Mm-KIR2DL5.2.
|
A novel KIR cDNA was identified that has a nucleotide sequence
that appears to encode a molecule with D1 and D2 Ig domains and a
cytoplasmic tail that is similar in length to KIR2DL4. However, when
translated, this molecule only aligns with the signal sequence, D1
domain, and the first two-thirds of the D2 domain of Mm-KIR3DL (Fig. 7). Because of a frame shift, the
predicted amino acid sequence then changes to a novel domain of 55 aa,
and the molecule terminates at a final length of 244 aa. Because this
molecule has only one complete Ig domain and no recognizable
cytoplasmic tail, we have designated it Mm-KIR1D.
|
Multiple splice variants of Mm-KIR1D were detected. In particular,
three different deletions of the D2 domain were found (Fig. 8). Mm-KIR1Dsv4 has a deletion of 176 nt
in D2 that results in a 2-nt frame shift. The predicted 32 aa of the D2
domain in this molecule align with Mm-KIR3DL. Its stem, transmembrane,
and cytoplasmic domains are unique, but homologous to those of other
KIR molecules. Mm-KIR1Dsv6 has a deletion encompassing the entire D2
domain, but has stem, transmembrane, and cytoplasmic domains that are
identical with those of Mm-KIR1Dsv4. Mm-KIR1Dsv9 has a deletion of 115
nt in D2 and a resultant 1-nt frame shift. This frame-shifted molecule
terminates early, before the stem domain.
|
). The transmembrane domains of the splice variants, like those of the
human KIR3DL molecules, have one more amino acid than the homologous
domains of Mm-KIR3DL molecules. The cytoplasmic tails of the splice
variants have two ITIMs and are 27 aa longer than the cytoplasmic tails
of Mm-KIR3DL molecules. These cytoplasmic tails are 4 aa shorter than
the cytoplasmic tails of Mm-KIR2DL4 or Mm-KIR2DL5.
Mm-KIR1Dsv2 has a deletion of the exon encoding the transmembrane and
portions of the stem and cytoplasmic domains (exon 7 in human KIR3DL1;
Fig. 8). This 104-nt deletion results in a 2-nt frame shift. When
translated, this molecule has most of the cytoplasmic tail, including
the two ITIMs. The molecule Mm-KIR1Dsv8 has deleted both the D2 domain
and exon 7. The net effect of these deletions is a 1-nt frame shift
that, when translated, results in early termination. Finally, some of
the Mm-KIR1D splice variants, such as Mm-KIR1Dsv1, have a 12-aa
deletion at the beginning of the D1 domain.
Mm-KIR3DH and alternatively spliced forms
A second novel family of rhesus monkey KIR molecules was
identified (Fig. 9). Like Mm-KIR3DL, the
cDNA of these molecules encode three Ig domains. However, scattered
nucleotide changes occur in all three of the Ig domains that are
distinct from any Mm-KIR3DL molecule. Although these molecules have
three Ig domains, portions of the stem, transmembrane, and cytoplasmic
domains encoded by exon 7 are similar in sequence to the homologous
region of Mm-KIR2DL4.2. In particular, the transmembrane domains of
these novel rhesus monkey KIR molecules include an arginine as well as
the threonine in the stem and isoleucine in the transmembrane domains
that are characteristic of Mm-KIR2DL4.2. Nevertheless, these novel
molecules have amino acid changes in the transmembrane domain that are
distinct from Mm-KIR2DL4.2. The nucleotide sequence of exon 8 expected
in a KIR molecule is not found in these rhesus monkey KIR molecules.
This deletion of 53 nt leads to a 2-nt frame shift, and the novel
molecules terminate after encoding only two further amino acids. This
early termination occurs before the ITIMs seen in the Mm-KIR3DL and
Mm-KIR2DL4 molecules.
|
In defining a type of Mm-KIR3DH molecule on the basis of >2%
predicted amino acid sequence divergence between Mm-KIR3DH cDNA clones,
three distinct types of Mm-KIR3DH were detected in a single rhesus
monkey. In a second rhesus monkey, a fourth distinct Mm-KIR3DH molecule
was identified (Fig. 9).
Alternatively spliced forms of Mm-KIR3DH were identified in both of
these rhesus monkeys (Fig. 10). As seen
in Mm-KIR3DL splice variant molecules, Mm-KIR3DH molecules with
deletions of the D0 domain, 12 aa of D1, and 50 aa of D2 were detected.
The deletion of a portion of the stem seen in Mm-KIR3DHsv4 is similar
to the stem deletion of the human KIR3DL1 molecule NKB1B
(14). However, Mm-KIR3DHsv4 also has two additional
deletions in the Ig domains. A large deletion extending from the D2
domain to the end of the cytoplasmic domain is seen in Mm-KIR3DHsv5 and
Mm-KIR3DHsv6. This deletion, in combination with deletions in the D0 or
D1 domain, results in molecules with only one complete Ig domain and no
significant cytoplasmic tail. A further 27-aa deletion in the middle of
D1, in combination with the 12-aa deletion at the beginning of D1, is
unique to Mm-KIR3DHsv6. Mm-KIR3DHsv7 has a 176-nt deletion in the D2
domain that leads to a frame shift of 2 nt and subsequently to an early
termination.
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
). The most striking aspect of the
Mm-KIR3DL molecules in the monkey is their extreme polymorphism. Two
KIR3DL molecules have been described in humans, and five distinct forms
of KIR3DL have been identified in chimpanzees (14, 25, 26). The two human KIR3DL molecules are quite distinct from one
another, differing in sequence by 75 aa. However, when sequences of
KIR3DL1 molecules from different individuals are compared, fewer than
five amino acid differences are detected (18, 19).
Similarly, the nucleotide sequences of the same type of Pt-KIR3DL
molecule are quite similar (<2% differences) when sequences from
different chimpanzees are compared (25). In contrast to
this, the sequences of the KIR3DL molecules identified in the rhesus
monkey are strikingly variable when molecules from different animals
are compared. Up to five forms of Mm-KIR3DL molecules were detected in
a single rhesus monkey, and eleven distinct Mm-KIR3DL molecules were
found in the five animals studied (Fig. 3). It is noteworthy that the
five Mm-KIR3DL molecules detected in monkey 227 have predicted amino
acid sequences that differed by >2% from all three of the KIR3DL
molecules detected in monkey 577.
|
).
Although a single form of KIR2DL4 has been defined in humans and
chimpanzees, two forms of Mm-KIR2DL4 were identified. These two forms
of Mm-KIR2DL4 have identical Ig domains, but the ends of their
cytoplasmic tails differ as a result of a single nucleotide deletion.
In contrast to both the human and chimpanzee KIR2DL4 molecules that
have only one ITIM, these rhesus monkey molecules contain two ITIMs in
their cytoplasmic domains (Fig. 5). It is possible that the function of
the two Mm-KIR2DL4 molecules may differ because of differences in their
cytoplasmic tails; however, no interaction with signaling proteins
outside the ITIMs has been described for the cytoplasmic tails of the
human KIR molecules.
The novel Mm-KIR3DH molecules have three Ig domains like the Mm-KIR3DL
molecules, but lack ITIMs in their cytoplasmic tails because of an exon
8 deletion. Lacking ITIMs, they are not likely to act as inhibitory
receptors. Rather, Mm-KIR3DH molecules may act as activating receptors
for rhesus monkey NK cells. These receptors have a transmembrane domain
that is most similar to the transmembrane domain of the Mm-KIR2DL4.2
molecule, which contains an arginine. The charged amino acid arginine
in the transmembrane domains of the Mm-KIR3DH molecules may be capable
of interacting with proteins that have an immunoreceptor tyrosine-based
activation motif, such as DAP12 or FcR
. In fact, the activating
forms of the ILT and Ly49 receptor families both contain an arginine in
their transmembrane domains that interacts with FcR and DAP12,
respectively (29, 30). This suggests that an arginine may
substitute in these monkey KIR molecules for the lysine seen in the
activating form of the human KIR molecules. Nevertheless, an arginine
is also seen in the transmembrane domains of the human and rhesus
monkey KIR2DL4 molecules. These molecules have ITIMs, and are presumed
to mediate inhibitory signaling.
Comparison of the D1 and D2 domains of the Mm-KIR3DH molecules with the
human KIR2DL2 crystal structure revealed amino acid differences among
the four types of Mm-KIR3DH in all but the first of the loops that are
likely to interact with the MHC ligand (28). Loop 5 in the
D2 domain is particularly variable, with four different amino acids at
position 251 for the four different Mm-KIR3DH types (Fig. 9).
Multiple splice variants of Mm-KIR3DL and Mm-KIR3DH molecules were
detected (Figs. 4 and 10). Most of these deletions remained in the same
reading frame as the full-length KIR molecules. Many of these deletions
correspond to exon boundaries and would occur as the result of exon
skipping. Deletions of only portions of the Ig domains also were
identified. These variants may be produced through the use of
alternative splice sites, as has been suggested for the human KIR
splice variants (24). These molecules with deletions in
the Ig domains may have altered binding to their MHC ligands. In
addition, because these deletions result in the elimination of 
sheets, the folding of these molecules is likely to be affected.
Spliced forms also were identified that lack stem and transmembrane
domains. These molecules may be soluble. However, it remains unclear
whether any of the alternatively spliced Mm-KIR molecules have a
biological function.
Because a PCR-based approach was used to characterize the KIR molecules of rhesus monkeys, rare mRNA forms could have been preferentially amplified, resulting in a distortion of the relative representation of these transcripts. Conversely, other KIR molecules may not have been amplified by the PCR primers used in this study. Indeed, certain KIR molecules seen in both humans and chimpanzees were not observed in rhesus monkeys. We did not identify rhesus monkey homologues for KIR2DL with the D1-D2 configuration. Because these KIR molecules interact with HLA-C alleles in humans, and rhesus monkeys have been shown to lack a homologue for HLA-C, it is possible that there was no selection for the D1-D2 form of KIR2DL in the rhesus monkey (31). Interestingly, the Mm-KIR1D molecule has a complete D1 Ig domain and a portion of a D2 domain preceding a frameshift. This molecule may in fact be a homologue of the human KIR2DL molecules.
We also did not identify rhesus monkey KIR molecules with short cytoplasmic tails and a lysine in the transmembrane domain homologous to the activating KIR molecules seen in humans and chimpanzees. It remains possible that the rhesus monkey homologues of KIR2DS and KIR3DS are too divergent from the human activating KIR molecules to be identified by using the human KIR-specific PCR primers. However, Mm-KIR3DH molecules may be activating KIR molecules in rhesus monkeys.
Finally, evaluation of the Mm-KIR3DL molecules revealed no homologues of the human KIR3DL2 molecule, which has two characteristic cysteines at amino acid positions 302 and 336. It has been suggested that one of these cysteines facilitates homodimerization of the KIR3DL2 molecule (26). Interestingly, cysteines in these positions were not found in any of the chimpanzee or rhesus monkey KIR molecules. These findings suggest that a homodimerized form of a KIR3DL molecule may not exist in primates other than humans.
In addition to the KIR molecules, the heterodimeric CD94/NKG2 family of molecules is a second type of MHC class I receptor expressed on human NK cells. The CD94/NKG2 receptor family recently has been characterized in rhesus monkeys (32). Both the inhibitory NKG2A and the activating NKG2C molecules were identified in this species, and these molecules have at least 85% amino acid identity to their human homologues. In humans, the ligand for these receptors is the nonclassical MHC class I HLA-E molecule (33). The homologue of HLA-E, Mamu-E, has also been identified in rhesus monkeys (34). Because HLA-E homologues in primates have limited polymorphism and are the most phylogenetically conserved of the MHC class I genes, it is not surprising that the NKG2 family is more conserved than the KIR molecules (35).
Although the extreme diversity of the rhesus monkey KIR molecules may be unexpected in view of our knowledge of their chimpanzee and human homologues, it may be readily appreciated in the context of our understanding of the classical MHC class I molecules of rhesus monkeys, the presumed ligand for most of the rhesus monkey KIR molecules. There appears to have been a duplication of the homologues of HLA-A and HLA-B, as well as the evolution of a novel MHC class I locus termed Mamu-I in this species (31, 36). This diversity of MHC class I molecules may have led to selection for a considerable number of KIR molecules, particularly Mm-KIR3DL molecules. Thus, the complexity of the rhesus monkey KIR molecules highlights their coevolution with their MHC ligands, as well as the rapidity of their evolution in primates.
|
Acknowledgments |
|---|
|
Footnotes |
|---|
2 The sequences presented in this paper have been submitted to GenBank and assigned the following accession numbers: AF334616–AF334626 (Mm-KIR3DL), AF334627–AF334633 (Mm-KIR3DLsv), AF334634 (Mm-KIR1D), AF334635–AF334643 (Mm-KIR1Dsv), AF334644 and AF334645 (Mm-KIR2DL4), AF334646 and AF334647 (Mm-KIR2DL5), AF334678–AF334651 (Mm-KIR3DH), and AF334652–AF334658 (Mm-KIR3DHsv).
3 Address correspondence and reprint requests to Dr. Norman Letvin, Department of Medicine, Division of Viral Pathogenesis, Beth Israel Deaconess Medical Center, Harvard Medical School, RE113, P.O. Box 15732, Boston, MA 02215.
4 Abbreviations used in this paper: KIR, killer cell Ig-like receptor; ITIM, immunoreceptor tyrosine-based inhibition motif; RACE, rapid amplification of cDNA ends.
Received for publication November 9, 2000. Accepted for publication January 24, 2001.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
-chain. J. Immunol. 162:5.This article has been cited by other articles:
|
|
 |
|
  P. Bostik, J. Kobkitjaroen, W. Tang, F. Villinger, L. E. Pereira, D. M. Little, S. T. Stephenson, M. Bouzyk, and A. A. Ansari Decreased NK Cell Frequency and Function Is Associated with Increased Risk of KIR3DL Allele Polymorphism in Simian Immunodeficiency Virus-Infected Rhesus Macaques with High Viral Loads J. Immunol., March 15, 2009; 182(6): 3638 - 3649. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. N. Bimber, A. J. Moreland, R. W. Wiseman, A. L. Hughes, and D. H. O'Connor Complete Characterization of Killer Ig-Like Receptor (KIR) Haplotypes in Mauritian Cynomolgus Macaques: Novel Insights into Nonhuman Primate KIR Gene Content and Organization J. Immunol., November 1, 2008; 181(9): 6301 - 6308. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. T.C.C. Patrao, D. B.C. Queiroz, G. Grossman, P. Petrusz, M. d. F. M. Lazari, and M. C. W. Avellar Cloning, expression and immunolocalization of {alpha}1-adrenoceptor in different tissues from rhesus monkey and human male reproductive tract Mol. Hum. Reprod., February 1, 2008; 14(2): 85 - 96. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. A. Guethlein, A. M. Older Aguilar, L. Abi-Rached, and P. Parham Evolution of Killer Cell Ig-Like Receptor (KIR) Genes: Definition of an Orangutan KIR Haplotype Reveals Expansion of Lineage III KIR Associated with the Emergence of MHC-C J. Immunol., July 1, 2007; 179(1): 491 - 504. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Mavilio, J. Benjamin, D. Kim, G. Lombardo, M. Daucher, A. Kinter, E. Nies-Kraske, E. Marcenaro, A. Moretta, and A. S. Fauci Identification of NKG2A and NKp80 as specific natural killer cell markers in rhesus and pigtailed monkeys Blood, September 1, 2005; 106(5): 1718 - 1725. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. G. Sambrook, A. Bashirova, S. Palmer, S. Sims, J. Trowsdale, L. Abi-Rached, P. Parham, M. Carrington, and S. Beck Single haplotype analysis demonstrates rapid evolution of the killer immunoglobulin-like receptor (KIR) loci in primates Genome Res., January 1, 2005; 15(1): 25 - 35. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. I. Khakoo, C. L. Thio, M. P. Martin, C. R. Brooks, X. Gao, J. Astemborski, J. Cheng, J. J. Goedert, D. Vlahov, M. Hilgartner, et al. HLA and NK Cell Inhibitory Receptor Genes in Resolving Hepatitis C Virus Infection Science, August 6, 2004; 305(5685): 872 - 874. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Daza-Vamenta, G. Glusman, L. Rowen, B. Guthrie, and D. E. Geraghty Genetic Divergence of the Rhesus Macaque Major Histocompatibility Complex Genome Res., August 1, 2004; 14(8): 1501 - 1515. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
|
|
R. Rajalingam, P. Parham, and L. Abi-Rached Domain Shuffling Has Been the Main Mechanism Forming New Hominoid Killer Cell Ig-Like Receptors J. Immunol., January 1, 2004; 172(1): 356 - 369. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. J. Pando, C. M. Gardiner, M. Gleimer, K. L. McQueen, and P. Parham The Protein Made from a Common Allele of KIR3DL1 (3DL1*004) Is Poorly Expressed at Cell Surfaces due to Substitution at Positions 86 in Ig Domain 0 and 182 in Ig Domain 1 J. Immunol., December 15, 2003; 171(12): 6640 - 6649. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Kikuchi-Maki, S.-i. Yusa, T. L. Catina, and K. S. Campbell KIR2DL4 Is an IL-2-Regulated NK Cell Receptor That Exhibits Limited Expression in Humans but Triggers Strong IFN-{gamma} Production J. Immunol., October 1, 2003; 171(7): 3415 - 3425. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
 |
|
 S. I. Khakoo, R. Geller, S. Shin, J. A. Jenkins, and P. Parham The D0 Domain of KIR3D Acts as a Major Histocompatibility Complex Class I Binding Enhancer J. Exp. Med., October 7, 2002; 196(7): 911 - 921. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. A. Guethlein, L. R. Flodin, E. J. Adams, and P. Parham NK Cell Receptors of the Orangutan (Pongo pygmaeus): A Pivotal Species for Tracking the Coevolution of Killer Cell Ig-Like Receptors with MHC-C J. Immunol., July 1, 2002; 169(1): 220 - 229. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Faure and E. O. Long KIR2DL4 (CD158d), an NK Cell-Activating Receptor with Inhibitory Potential J. Immunol., June 15, 2002; 168(12): 6208 - 6214. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S.-i. Yusa, T. L. Catina, and K. S. Campbell SHP-1- and Phosphotyrosine-Independent Inhibitory Signaling by a Killer Cell Ig-Like Receptor Cytoplasmic Domain in Human NK Cells J. Immunol., May 15, 2002; 168(10): 5047 - 5057. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. G. Shilling, L. A. Guethlein, N. W. Cheng, C. M. Gardiner, R. Rodriguez, D. Tyan, and P. Parham Allelic Polymorphism Synergizes with Variable Gene Content to Individualize Human KIR Genotype J. Immunol., March 1, 2002; 168(5): 2307 - 2315. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Rajagopalan, J. Fu, and E. O. Long Cutting Edge: Induction of IFN-{gamma} Production but Not Cytotoxicity by the Killer Cell Ig-Like Receptor KIR2DL4 (CD158d) in Resting NK Cells J. Immunol., August 15, 2001; 167(4): 1877 - 1881. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
