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Department of Structural Biology, Stanford University, Stanford, CA 94305
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Abstract |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionDisclosuresReferences |
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The KIR locus and the leukocyte Ig-like receptor (LILR) locus form part of the leukocyte receptor complex on human chromosome 19 (4). The KIR genes are closely packed and separated by small, homologous intervening sequences. This organization facilitates unequal crossing over, one mechanism that has contributed to the abundant variability in human KIR haplotypes. KIR haplotypes differ in gene number (
5–15) and content, importantly in the relative numbers of genes encoding activating and inhibitory receptors (5). Most of the KIR genes exhibit allelic polymorphism and this serves to diversify KIR haplotypes further.
KIR genes encode receptors that differ in specificity for HLA class I ligands and signaling potential. Well recognized are the specificities of KIR2DL1, 2DL2, 2DL3 and KIR2DS1 for HLA-C, KIR3DL1 for HLA-B, and KIR3DL2 for HLA-A (6, 7, 8). Clinical correlations with infection, autoimmunity, and transplantation implicate other KIR as having common HLA class I ligands, but these specificities have yet to be confirmed by biochemical or cellular analysis. Although it is clear that KIR can distinguish between groups of allotypes of an HLA locus, a pressing and largely unanswered question is: do KIR allotypes differ in their recognition of an HLA class I ligand?
In studying this question the KIR3DL1 locus has several experimental advantages such as high polymorphism (i.e., many distinct allotypes), defined HLA-B ligands, inhibitory function, and specific mAbs, which do not cross-react with other KIR. Moreover, flow cytometric analysis has shown that different KIR3DL1 alleles define different levels of cell surface expression, which points to the allotypes having functional difference (9). One special case is the 3DL1*004 allele, for which the protein is made but is retained within the cell (10); a second special case is KIR3DS1, which segregates as an allele of the KIR3DL1 gene but has potential activating rather than inhibitory function (11). So far KIR3DS1 has resisted biochemical and immunological characterization, but an analysis of HIV-infected patients found the combination of KIR3DS1 and a presumptive Bw4 ligand to be correlated with slower progression to AIDS (12).
The goal of the investigation we describe was to compare the functional recognition of HLA-Bw4 by two KIR3DL1 allotypes that are both inhibitory receptors and expressed at the cell surface, but which differ at selected positions.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionDisclosuresReferences |
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PBMC samples were obtained from healthy human donors by informed consent under an Institutional Review Board approved protocol. 3DL1*007 (AF262973) was isolated as described (2) and subcloned into a retroviral vector pMX-puro (13), which is a gift from Dr. T. Kitamura (The Institute of Medical Science, University of Tokyo, Tokyo, Japan). NK leukemia (NKL) cells, a gift from Dr. M. Robertson (Department of Medicine, Indiana University, Indianapolis, IN) (14), were transduced to express KIR using the Phoenix Helper dependent protocol as described by Gary Nolan (
www.stanford.edu/group/nolan/protocols/pro_helper_dep.html
). KIR3DL1 mutants were generated using the Quick Change site-directed mutagenesis kit (Stratagene) according to the manufacturer’s instructions. The NKL 3DL1*002 cell line, which was produced by transduction of NKL with the 3DL1*002 (U31416) pMX retroviral vector, was generously provided by Dr. L. Lanier (University of California, San Francisco, CA).
PE-labeled, NK cell receptor-specific Abs anti-KIR3DL1 mAb DX9 (DNAX); anti-KIR2DL1 mAb EB6 (Corixa); anti-CD94 mAb HP3D9 (BD Biosciences); anti-NKG2A mAb Z199 (Corixa); and unconjugated anti-LILRB1 mAb HP-F1, a gift from M. López-Botet (Universitat Pompeu Fabra (DCEXS), Barcelona, Spain) with PE-labeled goat anti-mouse F(ab')2 were used to characterize the NKL cell lines by flow cytometry. KIR+ NKL cell lines were sorted for equivalent KIR expression with a FACStar cell sorter and clone-Cyt software and hardware (BD Biosciences).
Cultured NK cells were derived by the coculture of PBMC with irradiated RPMI 8866 cells as described (15). Following this expansion and subsequent enrichment by the MACS NK Cell Isolation kit (Miltenyi Biotec) per the manufacturer’s instructions, 3DL1*002+/LILRB1– NK cells were sorted with a FACStar cell sorter and maintained in RPMI 1640 medium supplemented with 10% FBS, 2 mM glutamine (Invitrogen Life Technologies), 100 U/ml penicillin/streptomycin (Invitrogen Life Technologies), and 100 U/ml rIL-2 (National Institutes of Health, National Cancer Institute Preclinical Repository, Frederick, MD).
Cytolytic assays
Cell killing assays (i.e., 4-h 51Cr release assays) were performed as described (16) using KIR transduced NKL cell lines or polyclonal NK cell lines as effectors and 51Cr-labeled target cells: 721.221 (untransfected) and 721.221 (transfectants) expressing individual HLA class I allotypes that have been previously described (7). PE-conjugated, pan-HLA-specific mAb W6/32 (17) was used to assess and sort for equivalent class I expression on the 221 transfectants. Unconjugated Abs (anti-HLA mAb DX17 (DNAX), anti-LILRB1 mAb HP-F1, and anti-KIR3DL1 mAb DX9) were used as blocking reagents in cell killing assays at a concentration of 25 µg/ml per well.
Data analysis
Where appropriate, results were presented as specific lysis or the percentage of inhibition of lysis (IOL) relative to the lysis of 721.221 to normalize lytic activity between the cell lines and adjust for variation in the lysis of the 721.221 cell line. The percentage of IOL was calculated with the following formula: [1 – (percent-specific lysis of target cells)/(mean of percent-specific lysis of 721.221)] x 100. Additionally, some results were presented as the relative percentage of IOL compared with lysis by a control NKL cell line. All effectors lysed untransfected 221 target cells at levels exceeding 30% at an E:T ratio of 20:1, and the background spontaneous release for all targets was <15%.
A predicted model of 3DL1*002 (Accession no. U31416) was generated with Swiss Model (www.expasy.org/swissmod/SWISS-MODEL.html) (18). In this model the D0 domain was modeled separately from the D1 and D2 domains and the complete structure was assembled and viewed using Deep View and MolScript version 2.1 programs, respectively (www.avatar.se/molscript.html).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionDisclosuresReferences |
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KIR3DL1 transduced NKL cell lines reproduce predicted HLA specificities
Retroviral transduction was used to make lines of NKL cells that stably express 3DL1*002 and 3DL1*007. Cell sorting was used to produce transductants expressing comparable amounts of 3DL1*002 and 3DL1*007 at the cell surface (Fig. 2A). Using anti-KIR3DL1 Ab titration we observed no difference in Ab staining between the two KIR3DL1 variants (data not shown), suggesting equivalent Ab affinities. KIR transduced and untransduced NKL cells were compared for their capacity to kill 721.221 cells transfected with B*5101, a Bw4+ ligand for the KIR3DL1 receptor, and with B*1502, a Bw6+ allotype. As expected, B*5101 elicited stronger lysis inhibition from NKL cells expressing the KIR3DL1 variants than from untransduced NKL cells (Fig. 2B). For NKL cells expressing either 3DL1*002 or 3DL1*007, stronger lysis inhibition occurred with B*5101 than with B*1502, although the latter was reproducible. Gumperz et al. (7) also found that some KIR3DL1+ NK cell clones were specifically inhibited by B*1502, but these same clones were significantly more inhibited by Bw4 allotypes (7). Thus, our data were consistent with previous descriptions of KIR3DL1 specificity for Bw4 HLA-B. Based on these data and previous descriptions of LILRB1 recognition of HLA-B allotypes (20, 21), we attributed inhibition of untransduced NKL cells to LILRB1 expression. However the observed differences in response between KIR3DL1 transduced and untransduced NKL cells were not due to differences in LILRB1 expression because LILRB1 expression was equivalent for transduced and untransduced NKL cells (Fig. 2C).
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The response of these primary NK cells was consistent with the specificities of the 3DL1*002+ NKL cells (Fig. 2E). The ranking of the inhibitory response elicited relative to 721.221 lysis was B*5101>B*2705>B*1502 from greatest to least lysis inhibition consistent with data from previous studies (7, 22). None of these class I allotypes (i.e., B*5101, B*2705, or B*1502) had a canonical signal sequence that was permissive for CD94:NKG2A ligand expression (19). Thus, we found that some HLA-B ligands for 3DL1*002 elicited stronger inhibitory responses than others.
Differences between 3DL1*002 and 3DL1*007 alter receptor strength
To distinguish inhibition due to KIR3DL1 from that due to LILRB1, assays were performed in the presence and absence of specific mAbs. In the absence of receptor blocking Abs, lysis of all three NKL cell lines was inhibited, though less so for NKL than for the two transductants. In the presence of anti-LILRB1 mAb a clear hierarchy of inhibition was seen: NKL expressing 3DL1*002 > NKL expressing 3DL1*007 > untransduced NKL cells (Fig. 3). Thus, interaction of HLA-B*5101 with 3DL1*002 generates a stronger inhibitory response than interaction of HLA-B*5101 with 3DL1*007. This difference was most evident by the percentage of lysis inhibition relative to lysis of 721.221 (Fig. 3B). Because the expression levels of the two KIR3DL1 allotypes were comparable, this difference demonstrates that one or more of the amino acid substitutions that distinguish 3DL1*002 from 3DL1*007 make it a stronger receptor for HLA-B*5101.
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When anti-KIR3DL1 mAb was added to the cytolytic assay, lysis inhibition caused by B*5101 binding to 3DL1*002 or 3DL1*007 was partially blocked, whereas there was no affect on inhibition in the untransduced NKL parental cell line (Fig. 3). In contrast, when both anti-LILRB1 and anti-KIR3DL1 mAbs were included there was an equivalently strong blockade of inhibition of NKL cells expressing 3DL1*002 or 3DL1*007 and the parental cell line that was comparable to that observed in the presence of anti-HLA class I mAb. Thus, in the NKL cell transductants that express both LILRB1 and KIR3DL1, lysis inhibition is the consequence of both receptors recognizing the same HLA ligand. Individually, the inhibition mediated by LILRB1 is stronger than that mediated by KIR3DL1; however, when one of these receptors is blocked (e.g., LILRB1) the other receptor (e.g., 3DL1*002) can compensate to inhibit lysis. Functional differences between the KIR3DL1 variants were only apparent when the effects of LILRB1 were removed by the presence of anti-LILRB1 Ab. When LILRB1 function was not blocked (i.e., in the presence of a control Ab or no Ab) we did not observe differences between the KIR3DL1 variants. This outcome suggests that LILRB1 can compensate for functional differences between 3DL1*002 and 3DL1*007.
On interaction with HLA-Bw4, 3DL1*002 gives stronger inhibition of cytotoxicity than 3DL1*007
The removal of LILRB1-mediated inhibition revealed allotype differences in the inhibitory response to B*5101. Specifically, cells expressing 3DL1*002 were more inhibited than those expressing 3DL1*007. However, the question of whether this was a general phenomenon or specific to 3DL1*002-HLA B*5101 interactions remained unresolved. To address this issue, we compared the inhibitory responses generated by B*5101 to those generated by another Bw4+ HLA-B allotype, B*2705 (Fig. 4). Again, we used anti-LILRB1 mAb to exclude the contributions of LILRB1 to lysis inhibition. As in previous experiments with B*5101, both 3DL1*002- and 3DL1*007-expressing cell lines were more inhibited than untransduced NKL cells in the presence of either a control Ab or no Ab (p < 0.01) (Fig. 4A). By comparison, B*2705 elicited no difference between 3DL1*007-expressing and untransduced NKL cells, but did increase the inhibition through 3DL1*002. The levels of class I expression were equivalent between the B*5101 and B*2705 transfectants (Fig. 4B). Thus, we attributed the differences in inhibitory response to intrinsic differences in the HLA-B ligands. We found that B*5101 elicited a stronger inhibitory response than B*2705. This finding confirms previous observations made by Cella et al. (22).
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The functional difference between 3DL1*002 and 3DL1*007 is determined by polymorphism at position 238 in the D2 domain and position 320 in the transmembrane region
The 3DL1*002 and 3DL1*007 allotypes differ at three positions in the amino acid sequence: 238 in the D2 domain, 320 in the transmembrane region at the junction of the extracellular and transmembrane domains, and 373 in the cytoplasmic tail (Fig. 5A) (9). To determine the contribution of each position to the phenotypic difference we made a panel of six mutants, three from 3DL1*002 and three from 3DL1*007, in which each mutant had one position changed to the residue present in the other KIR3DL1 allotype (Fig. 5B). These mutants were transduced into NKL cells and the transductants sorted to obtain cells having comparable levels of KIR3DL1 expression at the surface (Fig. 5C). The mutant and the wild-type KIR3DL1 were then compared for their inhibitory capacity in cytolytic assays using 721.221-B*2705 target cells and inclusion of anti-LILRB1 mAb. The lysis obtained with transductants expressing KIR3DL1 variants and mutants was compared with that obtained with untransduced NKL cells.
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As none of the mutants having a single residue change altered the phenotype completely, four further mutants of 3DL1*002 were made: three had the various combination of two amino acid substitutions, the fourth had all three substitutions and served as a control (Fig. 5F). As done previously, the mutants were sorted for equivalent KIR3DL1 expression (data not shown). To determine the relative impact of these double and triple substitutions in 3DL1*002 the data were normalized to wild-type 3DL1*007 (Fig. 5, G and H). As predicted from the results obtained from the single residue mutants, the double mutant of 3DL1*002 with substitution at positions 238 and 320 gave no inhibition, like 3DL1*007 and the triple mutant, whereas the two other double mutants retained some inhibitory capacity. In conclusion, substitution at position 238 in the D2 domain and position 320 in the transmembrane region contribute to 3DL1*002 being a stronger inhibitory receptor than 3DL1*007, with each position making a comparable contribution to the difference.
To further understand how these residues influenced inhibitory function we generated a predicted molecular model of 3DL1*002 based on established KIR2D crystal structures (23, 24). In the KIR2D/HLA co-crystal structures ligand binding is localized to KIR residues in the interdomain hinge region. In our model we found that residue 238 in the D2 domain was distant from the putative ligand-binding site in a loop opposite the interdomain hinge region (Fig. 6). Thus, we propose that the enhanced inhibitory effects of these residues are due to indirect influences on ligand recognition, rather than direct ligand interactions.
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Discussion |
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A proposed mechanism that invokes indirect effects on ligand binding has precedence in HLA polymorphism that influences CD8 binding. During T cell target engagement CD8 binds to the membrane proximal 
3 domain of class I on the opposing cell. A naturally occurring single amino acid polymorphism in HLA-A68 and HLA-B48 abrogates this binding (25, 26, 27). Apparent in the CD8-HLA co-crystal this polymorphism distorts a protruding loop of the 3 domain, although the polymorphic residue at position 245 is not directly involved in contact with CD8 (26). Thus we speculate that similar conformational changes may explain the impact of the KIR3DL1 polymorphism examined in this study.
Although residue 238 is distant from the putative binding site: in a loop of the D2 domain opposite the hinge between the D1 and D2 domains, a significant change at this position may alter the conformation of the ligand binding loops. The substitution of arginine for glycine at position 238 is a radical one: the arginine being found only in 3DL1*002 (9). In comparison, the substitution of isoleucine in 3DL1*002 for valine in 3DL1*007 at position 320 is a conservative one, but this position occurs at the boundary between extracellular and transmembrane domains. Thus, even conservative substitutions in this model could significantly alter conformation of the extracellular region. In this manner, both residues 238 and 320 have the potential to indirectly alter conformation of the binding site and thereby influence inhibitory function.
Conformational changes are not the only potential mechanism to explain the effects of KIR3DL1 polymorphism. An alternative mechanism for contribution of positions 238 and 320 to KIR3DL1 function is the facilitation of receptor oligomerization. Whereas researchers have speculated that KIR oligomerization occurs at the immune synapse, this has not been formally proven. Although several crystallographic structures have been determined for complexes of HLA-C with KIR2D (23, 24), no structure for a KIR3DL1 has been solved, either alone or in complex with HLA-Bw4. Several lines of evidence, including the importance of residue 80 in both HLA-B and HLA-C for KIR interaction (28, 29), suggest that the D1 and D2 domains of KIR3DL1 bind to HLA-Bw4 in analogous manner to the KIR2D-HLA-C interaction. The D0 domain of KIR3DL1 enhances the interaction in a manner that is poorly understood (30), but may also involve oligomerization of KIR-HLA-Bw4 complexes.
In the co-crystal structure of KIR2DL2 complexed with HLA-Cw3, two KIR2DL2 proteins (i.e., KIR-A and KIR-B) contact each other through D2 (KIR-A) and D1 (KIR-B) domain interactions, respectively (23). Although amino acid residues in the 
-strand loops of the D2 domain (i.e., I200, L119, E122, and V118) of KIR-A participate in KIR oligomerization, these residues do not correspond directly with position 238 of KIR3DL1 in our model of KIR3DL1 (Fig. 6). However, the presence of an additional extracellular domain (i.e., D0) may alter the conformation of the D2 domain of KIR3DL1. Thus, receptor oligomerization involving position 238 cannot be excluded completely without further evaluation.
In addition, the idea that amino acid residues in the transmembrane domain facilitate homotypic interactions during receptor oligomerization has precedence in other biological systems. In the gp41 envelope protein of HIV-1 a single isoleucine residue in the transmembrane domain is essential for receptor oligomerization and biological function and without it oligomerization does not occur (31). It is reasonable to predict that residue 320 of KIR3DL1 may play a similar role.
In summary, we propose two possible mechanisms by which naturally occurring polymorphism at positions 238 and 320 may influence KIR3DL1 function. In one proposed mechanism these residues determine distantly the conformation of ligand binding loops, and in another they determine receptor on receptor interactions at the cell surface. Based on our data, either of these models provides a reasonable framework for understanding KIR3DL1 polymorphism in the context of inhibitory function.
To eliminate the confounding effects of differing levels of cell surface expression we deliberately selected and studied NKL transductants that expressed equivalent levels of 3DL1*002 and 3DL1*007. This showed that 3DL1*007 is an inherently weaker Bw4 receptor than 3DL1*002. In nature 3DL1*007 is expressed at lower levels on human peripheral blood NK cell surfaces than 3DL1*002 (9), as assessed using the same anti-KIR3DL1 mAb used in this study to assess expression by NKL transductants. It is therefore expected that this difference in expression level will further amplify the functional difference in the inhibitory capacity of 3DL1*002 and 3DL1*007 that we have defined in our study.
We also provide the first evidence that LILRB1 and KIR both contribute to an inhibitory response to the same Bw4 HLA-B ligand. Previously, Willcox et al. (32) had predicted that KIR3DL1 and LILRB1 could simultaneously bind the same HLA molecule based on their HLA/LILRB1 co-crystal structure. From our data we conclude that LILRB1 and KIR3DL1 cooperate functionally, but we cannot tell whether this cooperation depended on interaction of the two receptors with the same HLA class I molecule. In general, both receptors rely upon the same molecules for signaling (21, 33).
Two models to explain the potential mechanism of LILRB1/KIR3DL1 cooperation can be considered. In one model, clustering of inhibitory synapse receptors that use the same signaling machinery amplifies the inhibitory signal. In another model, either LILRB1 or KIR3DL1 functions as an adhesion molecule (analogous to CD8) and prolongs the ligand binding of the receptor that initiates signaling. Distinguishing these models will require further analysis to compare lysis inhibition with receptors mutated to eliminate signaling function specifically.
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Acknowledgments |
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Disclosures |
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Footnotes |
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1 This work was supported by National Institutes of Health Grant AI22039 (to P.P.) and by National Institutes of Health, National Institute of Allergy and Infectious Diseases Grants K08 AI50779-01 and AI50779-02 (to W.H.C.). W.H.C. is a recipient of nonduplicating support from the United Negro College Fund, Merck Science Initiative Fellowship. 
2 Address correspondence and reprint requests to Drs. Peter Parham and William Henry Carr, Department of Structural Biology, Stanford University, Stanford, CA 94305-5126. E-mail address: peropa{at}stanford.edu Department of Microbiology and Immunology, University of California, San Francisco. E-mail address: wcarr{at}itsa.ucsf.edu
3 Abbreviations used in this paper: KIR, killer cell Ig-like receptor; LILR, leukocyte Ig-like receptor; NKL, NK leukemia; IOL, inhibition of lysis.
Received for publication April 8, 2005. Accepted for publication July 13, 2005.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionDisclosuresReferences |
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3 domain of HLA-A molecules affects binding to CD8. Nature 338:345.-347. [Medline]
() and HLA-A2. Nature 387:630.-634. [Medline]
. J. Biol. Chem. 275:15232.-15238. This article has been cited by other articles:
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  T. Graef, A. K. Moesta, P. J. Norman, L. Abi-Rached, L. Vago, A. M. Older Aguilar, M. Gleimer, J. A. Hammond, L. A. Guethlein, D. A. Bushnell, et al. KIR2DS4 is a product of gene conversion with KIR3DL2 that introduced specificity for HLA-A*11 while diminishing avidity for HLA-C J. Exp. Med., October 26, 2009; 206(11): 2557 - 2572. [Abstract] [Full Text] [PDF]
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G. Alter, M. P. Martin, N. Teigen, W. H. Carr, T. J. Suscovich, A. Schneidewind, H. Streeck, M. Waring, A. Meier, C. Brander, et al. Differential natural killer cell mediated inhibition of HIV-1 replication based on distinct KIR/HLA subtypes J. Exp. Med., November 26, 2007; 204(12): 3027 - 3036. [Abstract] [Full Text] [PDF]
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) and 721.221 cells transfected with HLA-A*0301 (
) or HLA-B*5101 (
) in the presence and absence of several mAbs. The E:T ratio was 20:1. Both anti-HLA class I and anti-LILRB1 mAbs abrogate the HLA-B*5101-mediated inhibition of cytolysis. No abrogation of lysis was caused by anti-CD94, although this mAb binds to NKL cells as shown in A. The assay shown represents two independent experiments in which SDs are indicated.
), 721.221 cells transfected with Bw6+ HLA-B*1502 (
) or Bw4+ HLA-B*5101 (
), or Bw4+ HLA-B*5101 (
