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*
Terry Fox Laboratory, British Columbia Cancer Agency, and Departments of
Medical Genetics and
Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada
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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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Ly-49C is unique among the Ly-49 molecules characterized to date. It binds a broad range of class I MHC. Furthermore, it is the only inhibitory receptor that has been identified on B6 NK cells that recognizes self (H-2b) class I MHC. It was originally cloned from (CBA x B6)F1 mice and was later found to be of CBA origin (7). An identical cDNA was isolated from BALB/c mice. Ly-49IB6 was cloned from B6 NK cells and was initially thought to be the B6 allelic form of Ly-49C due to its high degree of sequence similarity with Ly-49CBALB (3). Subsequently another Ly-49, which is more similar to Ly-49CBALB, has been cloned from B6 NK cells (8, 9), and the newly identified Ly-49 has been named Ly-49CB6. Both Ly-49CB6 and Ly-49IB6 are recognized by the 5E6 mAb that identifies a subset of NK cells involved in hybrid resistance (10). Treatment of irradiated (BALB/c x B6)F1 mice with 5E6 mAb prevents the rejection of H-2d, but not H-2b, parental bone marrow graft. Therefore, 5E6+ NK cells are thought to receive inhibitory signals from H-2b, but not H-2d, bone marrow graft. 5E6+ NK cells from B6 or (BALB/c x B6)F1 mice also readily kill H-2d, but not H-2b, Con A blasts (11). These results suggest that Ly-49 detected by the 5E6 mAb is an inhibitory receptor specific for H-2b, but not H-2d. This view is complicated by the finding that both Ly-49C and I are recognized by the 5E6 mAb (8). How Ly-49C and I regulate the rejection of bone marrow grafts in hybrid resistance remains to be elucidated. Interestingly, despite their similar amino acid sequences, they seem to differ significantly in their specificities for class I MHC. Ly-49CB6, like Ly-49CBALB, binds to a wide range of class I MHC, including Dd, as determined by the binding of cells expressing defined class I MHC to Ly-49C-transfected COS cells. In contrast, binding of Ly-49IB6 to class I MHC has not been detected by this method (8).
With very limited structural information available to provide insight into the basis of Ly-49C recognition of its various ligands, we have in this study identified the amino acid residues that are critical for mediating the recognition of class I MHC by engineering chimeras and mutants of Ly-49CB6 and IB6. The results provide some understanding of the structural basis for the recognition of class I MHC by the Ly-49 family of NK receptors.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The 34-5-8S (anti-Dd), 28-14-8S (anti-Db), 16-1-11S (anti-Kk), and 28-8-6S (anti-Kb) hybridomas as well as the rat basophilic leukemia line RBL-1 were obtained from American Type Culture Collection (Manassas, VA). The murine leukemic lines IC-21 (H-2b) and GM979 (H-2s) have been described previously (12). 5E6 mAb that recognizes Ly-49C and I as well as 4LO3311 mAb that recognizes Ly-49C have also been described (8, 10, 13).
Transfection of murine class I MHC into RBL-1
cDNAs encoding the murine class I MHC Dd, Kb, and Db were isolated by RT-PCR. The primers for the RT-PCR were designed based on the nucleotide sequences for these class I MHC molecules in GenBank. The cDNAs were subcloned into pBluescript, sequenced, and subcloned into the expression vector pBCMGS (14). Ten micrograms of class I MHC cDNAs in pBCMGS were electroporated into 3 x 106 RBL-1 cells suspended in 0.5 ml of DMEM at 440 V and 125 µFD. Transfectants were initially selected by 0.7 mg/ml G418 (Canadian Life Technologies, Burlington, Canada), and those expressing the appropriate murine class I MHC were isolated by panning with specific anti-class I MHC mAbs immobilized on bacteriological dishes. For the transfection of Kk, 4 µg of genomic DNA encoding Kk was used.
Generation of mutant and chimeric Ly-49C and I cDNAs
The Ly-49IB6 cDNA used in this study had a point mutation that converted histidine at position 193 to arginine, presumably due to a PCR error. This mutation did not change the binding specificity of Ly-49IB6. All the mutant Ly-49C and I as well as the chimeric Ly-49C/I cDNAs used in this study were generated by PCR, with the exception of the mutant Ly-49C cDNA mut10. This construct was generated by replacing an XbaI fragment of Ly-49C cDNA with the corresponding fragment from Ly-49I cDNA. For the generation of chimeric Ly-49 constructs, appropriate cDNA fragments were generated by PCR using PfuI DNA polymerase (Stratagene, La Jolla, CA) that generates blunt ends. Upstream PCR fragments were generated by using a 5' primer containing an EcoRI site and a phosphorylated 3' primer, whereas downstream PCR fragments were generated by using a phosphorylated 5' primer and a 3' primer containing a KpnI site. The PCR fragments were digested with EcoRI or KpnI and ligated with pBluescript digested with EcoRI and KpnI. The resultant clones were sequenced in their entirety. Point mutants were also generated in a similar manner using primers containing mutations. The chimeric and mutant cDNA clones were subcloned into the expression vector pAX114 and transfected into COS cells as previously described (4).
Binding assays
Binding of GM979 and IC-21 to Ly-49-transfected COS cells was determined as described previously (3). The same method was used to determine binding of class I MHC-transfected RBL-1 cells to Ly-49-transfected COS cells with the following minor modifications. Plates of COS cell cultures were preincubated with heat-treated BSA (0.5 mg/ml in HBSS) for 1 h at 37°C to prevent nonspecific binding of RBL-1 cells to plates. COS cells and RBL-1 cells were incubated for 15 min at room temperature, unbound cells were washed away, and bound cells were assessed by microscopic observation and, in some cases, photographed. The assays were performed in a blind fashion. For quantitative binding assays, transfected RBL-1 cells were labeled with 1 µCi/ml of tritiated thymidine for 24 h, and equivalent radioactive amounts were subsequently added to the COS cells in the presence or the absence of 5E6 mAb (25 µg/ml). After the unbound RBL-1 cells were removed, remaining bound cells were lysed with 10% Triton X-100 and counted in a scintillation counter. Specific cell binding was determined by the radioactivity of bound cells in the absence of 5E6 minus that in the presence of 5E6. The specific binding of the same constructs fluctuated from experiment to experiment due to variabilities in COS cell transfection efficiency, but the binding patterns among different Ly-49 constructs in each experiment were highly consistent and reproducible. Therefore, the results were expressed as relative binding using the binding of Ly-49C as 100%.
Flow cytometric analysis
Flow cytometric analysis of Ly-49-transfected COS cells stained with mAbs has been previously described (12). RBL-1 cells transfected with murine class I MHC were stained with appropriate anti-class I MHC mAbs and FITC-conjugated secondary Abs and subsequently analyzed by a FACScan flow cytometer (Becton Dickinson, Mountain View, CA).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We have previously reported that the deduced amino acid sequences
of Ly-49CB6 and Ly-49IB6 differ in 22 residues,
14 of which are in the extracellular domains (8). They also
significantly differed in the binding of class I MHC, as determined by
the binding of murine leukemic cell lines IC-21 (H-2b),
R1.1 (H-2k), A20 (H-2d), and GM979
(H-2s) to COS cells transfected with Ly-49CB6
or Ly-49IB6. Ly-49CB6 bound all the cell lines
tested, whereas none of them bound to Ly-49IB6. Here, we
have extended these studies by testing the binding of the rat leukemic
cell line RBL-1 transfected with Dd, Db,
Kb, or Kk. The expression of the transfected
class I MHC on RBL-1 as well as Ly-49C and I on COS cells was high
(Figs. 1
and 5). Microscopic observation
of the binding of class I MHC-transfected RBL-1 cells to
Ly-49-transfected COS cells showed very weak binding of Kb
and Dd to Ly-49I. However, quantitative binding assay
results from eight independent experiments showed that the binding of
these class I MHC to Ly-49I was too weak to be statistically
significant (Fig. 2), and none of the
remaining transfected RBL-1 lines significantly bound to Ly-49I. In
contrast, Ly-49C strongly bound all the class I MHC tested (Fig. 2),
but not to control RBL-1 cells transfected with vector cDNA alone.
Although the levels of specific binding (binding in the absence of the
blocking 5E6 mAb minus binding in the presence of 5E6) varied from
experiment to experiment, the binding of Ly-49C was highly
reproducible. Paired Student’s t test from eight
independent experiments showed that the binding of all class I
MHC-transfected RBL-1 lines to Ly-49C-transfected COS cells was
significantly (p < 0.05) higher than that to
control COS cells transfected with vector cDNA alone.
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The cell-cell binding results described above showed that
Ly-49CB6 and Ly-49IB6, despite their sequence
similarity, significantly differ in the binding of class I MHC. Each
receptor consists of a stalk region of 74 amino acids (residues
67–140) and a carbohydrate recognition domain
(CRD)3 of 126 amino acids
(residues 141–266). To determine the amino acid residues of
Ly-49CB6 that are critical for class I MHC binding
specificity, we generated a series of chimeric and mutant
constructs in which the amino acid residues of Ly-49C and I were
exchanged, as illustrated in Fig. 3A. The constructs were
transfected into COS cells and initially tested by binding assays using
GM979 (H-2s) and IC-21 (H-2b) cells. When the
entire CRDs of Ly-49C and I were exchanged (CI and IC in Fig. 3A), the IC construct, like Ly-49C, bound GM979 and IC-21,
whereas CI, like Ly-49I, did not bind these cell lines (Fig. 3, A and B). These results suggest that the CRD of
Ly-49CB6 confers its binding specificities. To determine
which amino acid residues in the CRDs are important for binding, we
generated a series of chimeric Ly-49C (IC2 to IC5 in Fig. 3A) in which progressively larger portions of the CRD of
Ly-49CB6 were replaced by the corresponding portions of
Ly-49I. Binding assays with GM979 and IC-21 cells showed that the
carboxyl-terminal region of 48 amino acids within the CRD of Ly-49C was
sufficient to convert the binding specificity of Ly-49I to that of
Ly-49C (IC4 in Fig. 3A). The chimera IC5, with an even
smaller portion of Ly-49C, did not seem to be expressed and, therefore,
did not bind to any of the cells tested.
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We also generated a series of Ly-49CB6 mutants in which
amino acid residues of Ly-49CB6 were replaced with the
corresponding residues of Ly-49IB6 (mut1–10 in Fig. 3
A) as well as a truncated Ly-49CB6 that lacked
the carboxyl-terminal 40 aa residues. The binding of GM979 and IC-21
cells to COS cells transfected with these Ly-49C mutants identified
three residues within the CRD that are critical for the binding. They
are tyrosine (Y) at position 146, which is six residues downstream of
the amino terminal of the CRD, and isoleucines (I) at positions 226 and
247, which are 40 and 19 residues upstream of the carboxyl terminal of
the CRD, respectively. The three mutant Ly-49CB6 expressing
these mutations, mut4, mut9, and mut10 (Fig. 3A), did not
bind GM979 cells, but all other mutants readily bound to the cell line.
Mut4 was generated by substituting tyrosine at position 146 with
histidine, and mut9 and 10 were generated by substitutions of
isoleucines with threonines at positions 226 and 247, respectively.
Results with IC-21 cells were similar for all mutants except mut10
(Fig. 3A).
Binding of class I MHC transfectants to chimeric and mutant Ly-49C/I
The above cell binding assays using GM979 and IC-21 identified the
amino acid residues of Ly-49C that are apparently important for the
binding of class I MHC. To further examine the effects of mutations at
these particular residues on the binding of class I MHC, we tested the
binding of various class I MHC-transfected RBL-1 to COS cells
expressing the chimeras and mutants IC, CI, IC6, IC7, mut4, mut9, and
mut10. Consistent with the previous binding results of GM979, the IC
chimera bound all class I MHC tested (Dd, Db,
Kb, or Kk), whereas the CI chimera was similar
to Ly-49I and did not significantly bind any of the RBL-1 transfectants
(Fig. 4). Particularly interesting were
IC7 and mut9. IC7 differs from Ly-49I in only two residues (at
positions 219 and 226) and yet was able to bind all class I MHC tested
to the level comparable to that of Ly-49C, with the only exception
being Dd, whose binding to IC7 was not statistically
significant. IC6, which differs from Ly-49I only in residue 219, did
not show binding to any of the class I MHC. Mut9 differs from Ly-49C in
only one residue (at position 226), but the binding of class I MHC
to this mutant was significantly reduced to a level comparable to that
of Ly-49I. Mut4 bound Db, Kb, and
Kk, but not Dd, whereas mut10 failed to bind
Dd.
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COS cells transfected with the chimeric/mutant Ly-49 described
above were also analyzed by flow cytometer using the 5E6 mAb that
detects both Ly-49C and Ly-49I as well as the 4LO3311 mAb that
recognizes Ly-49C, but not Ly-49I (8). The 4LO3311 mAb bound to Ly-49C
and Ly-49CI, but not to Ly-49IC (Fig. 5),
thus confirming the previous finding that this mAb binds to the stalk
region of Ly-49C (8). Staining of various mutant Ly-49C showed that
mut3, in which the lysine (K) residue at position 129 was
substituted with glutamic acid (E), was not recognized by 4LO3311
mAb (Fig. 5). Therefore, this lysine residue in the stalk region, 12
residues upstream of the boundary with the CRD, is critical for
recognition by the 4LO3311 mAb. Importantly, the 5E6 mAb did stain COS
cells expressing this mutant, indicating that it was expressed on the
cell surface.
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). It was, however, detected by the 4LO3311 mAb,
indicating that the mut7 protein was highly expressed. Both 5E6 and
4LO3311 mAbs failed to bind to mut11, in which the carboxyl-terminal 40
amino acid residues were deleted as well as the IC5 chimera. This was
probably due to the lack of cell surface expression of mut11 and the
IC5 chimera on the transfected COS cells, since none of the cell lines
used in this study bound to them. |
Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To identify the amino acid residues that are critical for the binding of Ly-49CB6 to its class I MHC ligands, we generated a series of chimeric and mutant Ly-49C/I for transfection into COS cells and subsequently tested their abilities to bind mouse class I MHC molecules expressed on a number of different cell lines. The results of the mutagenesis experiments revealed three putative sites that, when mutated, caused a significant decrease in ligand affinity. These are the tyrosine at position 146 and the two isoleucine residues at positions 226 and 247. A substitution of isoleucine at position 226 of Ly-49CB6 with the corresponding residue of Ly-49IB6, threonine, has a striking effect on the binding specificity. This mutant Ly-49CB6 (mut9) did not bind any of the class I MHC tested, indicating that this single residue substitution converts the specificity of Ly-49CB6 into that of Ly-49IB6. The binding specificity of Ly-49IB6 can also be changed by mutations in this region. Replacements of glutamine at position 219 and threonine at position 226 with proline and isoleucine, respectively, conferred upon the mutant Ly-49IB6 (IC7) the ability to bind Db, Kb, and Kk as well as GM979 and IC-21. Based on structural analyses of other lectin CRD domains (15), the residue I226 of Ly-49C corresponds to a position within one of the loop regions shown to be a highly variable and the least conserved region of the CRD compared with those of different Ly-49 molecules. If this variability is involved in conferring specificity of recognition to each Ly-49 member, it follows, then, that mutating I226 could alter the ligand specificity of Ly-49C.
The replacement of the residue isoleucine with threonine at position 247 generated the Ly-49C mut10. COS cells expressing this mutation bound Db and Kb, and this is consistent with its ability to bind the IC-21 cell line, which expresses the H-2b class I MHC haplotype. It also could recognize Kk. However, this mutation resulted in a significant reduction in binding to GM979 cells (H-2s) and RBL-1 cells expressing Dd, suggesting that I247 may contribute to the ligand specificity of Ly-49C for selective class I MHC molecules. Interestingly, structural and modeling data show that I247 resides at the C-terminal end of the fourth ß-strand of the CRD (15). No functional significance has been assigned to this domain of the CRD, although sequences adjacent to this region have been postulated to confer specificity differences between the E- and P-selectins (15, 16). To fully determine whether I247 has a role in selective ligand binding or in conferring specificity differences between Ly-49C and the other Ly-49 family members, further studies with a larger panel of class I MHC molecules are needed as well as mutagenesis studies of other Ly-49 in which a comparable site is targeted.
In addition to the above mutations, substituting the tyrosine at position 146 with histidine (mut4) at the carboxyl terminal of the CRD abrogates binding to GM979 and IC-21 cell lines as well as to Dd-transfected RBL-1 cells. Tyr146 is only six residues from the amino-terminal end of the CRD. While it is possible that the ligand specificity of Ly-49 may be influenced by sequences in this region, it is more likely that changes within this region indirectly affected ligand affinity by disrupting proper conformation of the CRD. The interpretation of these results is made more complicated by the fact that this Ly-49 mutant, mut4, was able to bind Db, Kb, and Kk. It is possible that IC-21 cells may require stronger avidity for binding, and this particular mutation may reduce the affinity to a nonbinding state. However, the mutation may not be disruptive enough to the RBL-1/Kb and Db transfectants. Furthermore, we have demonstrated that the binding of Dd to Ly-49C is not as great as that for the other class I transfectants, and this may explain why the Dd transfectants also did not bind to the Ly-49 mutant. However, without detailed structural information on Ly-49, the discrepancy in binding cannot be easily explained.
Flow cytometric analysis of COS cells transfected with the mutant and chimeric Ly-49s also identified the binding epitope for the 4LO3311 mAb, which binds to Ly-49CB6 but not IB6. The 4LO3311 mAb did not bind to the Ly-49CB6 mutant (mut3) in which lysine at position 129 was substituted by glutamic acid, indicating that the lysine residue is a critical part of the binding epitope for the 4LO3311 mAb. It is particularly interesting that this residue is 12 residues away from the CRD, yet 4LO3311 inhibits the binding of Ly-49C to class I MHC (8). The analysis of the binding of the 5E6 mAb also identified a critical amino acid residue. The 5E6 mAb bound less well to mut7, in which asparagine at position 198 of Ly-49CB6 was replaced by the corresponding residue of Ly-49IB6, serine. However, it was recognized by the 4LO3311 mAb, indicating that it was expressed on the surface of the transfected COS cells. Since the 5E6 mAb binds to both Ly-49C and I, it is not clear why this mutant was not strongly recognized by the 5E6 mAb. It is possible that 5E6 may recognize a conformation epitope, rather than a linear epitope, of the CRD, and the conformation may be disrupted by the mutations.
The crystal structure of Ly-49 has not yet been obtained. As stated earlier, direct structural data on Ly-49 is needed to elucidate fully how these NK receptors interact with class I MHC. Nevertheless, this study has demonstrated that the specificities of these receptors can be modulated by mutating critical amino acid residues and, therefore, provide useful information about their mode of interaction with class I MHC ligands.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Fumio Takei, Terry Fox Laboratory, British Columbia Cancer Research Center, 601 West 10th Avenue, Vancouver, British Columbia, Canada V5Z 1L3. E-mail address:
3 Abbreviation used in this paper: CRD, carbohydrate-recognition domain.
Received for publication December 11, 1998. Accepted for publication April 1, 1999.
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References |
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5 pre-B cell-specific genes can associate with each other and with µ heavy chain. J. Exp. Med. 172:969.This article has been cited by other articles:
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A. Kielczewska, H.-S. Kim, L. L. Lanier, N. Dimasi, and S. M. Vidal Critical Residues at the Ly49 Natural Killer Receptor's Homodimer Interface Determine Functional Recognition of m157, a Mouse Cytomegalovirus MHC Class I-Like Protein J. Immunol., January 1, 2007; 178(1): 369 - 377. [Abstract] [Full Text] [PDF]
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M. Maeda, C. Carpenito, R. C. Russell, J. Dasanjh, L. L. Veinotte, H. Ohta, T. Yamamura, R. Tan, and F. Takei Murine CD160, Ig-Like Receptor on NK Cells and NKT Cells, Recognizes Classical and Nonclassical MHC Class I and Regulates NK Cell Activation J. Immunol., October 1, 2005; 175(7): 4426 - 4432. [Abstract] [Full Text] [PDF]
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Y. Huang, F. Rezzoug, H. Xu, P. M. Chilton, C. L. Schanie, I. Fugier-Vivier, and S. T. Ildstad NK Cells Play a Critical Role in the Regulation of Class I-Deficient Hemopoietic Stem Cell Engraftment: Evidence for NK Tolerance Correlates with Receptor Editing J. Immunol., September 15, 2005; 175(6): 3753 - 3761. [Abstract] [Full Text] [PDF]
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B. J. Ma, E. T. Silver, B. Hazes, and K. P. Kane Reciprocal Transfer of Class I MHC Allele Specificity between Activating Ly-49P and Ly-49W Receptors by Exchange of {beta}4-{beta}5 Loop Residues J. Immunol., November 15, 2003; 171(10): 5337 - 5344. [Abstract] [Full Text] [PDF]
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J. Sundback, A. Achour, J. Michaelsson, H. Lindstrom, and K. Karre NK Cell Inhibitory Receptor Ly-49C Residues Involved in MHC Class I Binding J. Immunol., January 15, 2002; 168(2): 793 - 800. [Abstract] [Full Text] [PDF]
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L. Fahlen, U. Lendahl, and C. L. Sentman MHC Class I-Ly49 Interactions Shape the Ly49 Repertoire on Murine NK Cells J. Immunol., June 1, 2001; 166(11): 6585 - 6592. [Abstract] [Full Text] [PDF]
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 M. Imboden, K. R. Murphy, A. L. Rakhmilevich, Z. C. Neal, R. Xiang, R. A. Reisfeld, S. D. Gillies, and P. M. Sondel The Level of MHC Class I Expression on Murine Adenocarcinoma Can Change the Antitumor Effector Mechanism of Immunocytokine Therapy Cancer Res., February 1, 2001; 61(4): 1500 - 1507. [Abstract] [Full Text]
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A. Kubota, R. H. Lian, S. Lohwasser, M. Salcedo, and F. Takei IFN-{gamma} Production and Cytotoxicity of IL-2-Activated Murine NK Cells Are Differentially Regulated by MHC Class I Molecules J. Immunol., December 15, 1999; 163(12): 6488 - 6493. [Abstract] [Full Text] [PDF]
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