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Cutting Edge |
Production but Not Cytotoxicity by the Killer Cell Ig-Like Receptor KIR2DL4 (CD158d) in Resting NK Cells
Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResults and DiscussionReferences |
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upon contact with sensitive target cells. The
regulation of these effector responses in resting NK cells is not well
understood. We now describe a receptor, KIR2DL4, that has the unique
property of inducing IFN- production, but not cytotoxicity, by
resting NK cells in the absence of cytokines. In contrast, the NK
cell-activation receptors CD16 and 2B4 induced cytotoxicity but not
IFN- production. The induction by KIR2DL4 of IFN- production by
resting NK cells was blocked by an inhibitor of the p38
mitogen-activated protein kinase signaling pathway, in contrast to the
IL-2-induced IFN- secretion that was sensitive to inhibition of the
extracellular signal-regulated kinase mitogen-activated protein kinase
pathway. These results reveal a functional dichotomy (cytokine
production vs cytotoxicity) in the response of resting NK cells, as
dictated by the signals of individual
receptors. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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(1), it is unclear which receptors
contribute to activation of resting NK cells upon contact with target
cells and whether independent signals can uncouple the induction of
cytokine production from a cytotoxic response. The interaction of
activated NK cells with target cells can induce cytotoxicity and
IFN- production, depending on the outcome of signals from activating
and inhibitory receptors (2, 3, 4). Target cell lysis can be induced by Ab-dependent cellular toxicity through CD16 or by activation receptors such as NKp46, 2B4 (CD244), and others. Human NK cells express killer cell Ig-like receptors (KIR)2 and lectin-like receptors (CD94/NKG2) that recognize MHC class I ligands and either inhibit or activate NK cytotoxicity (5). Inhibitory receptors have immunoreceptor tyrosine-based inhibition motifs (ITIMs) in their cytoplasmic tails, whereas activating receptors lack the ITIM and pair with the immunoreceptor tyrosine-based activation motif-containing signaling partner DAP12 via charged amino acids in the transmembrane region (4).
KIR2DL4 (hereafter referred to as 2DL4) is a KIR family member
(recently designated CD158d) that shares structural features with both
activating and inhibitory receptors (6). 2DL4 has a
cytoplasmic ITIM, suggesting inhibitory function, and a positively
charged amino acid in the transmembrane region, a feature typical of
activating KIR. Unlike other clonally distributed KIRs, 2DL4 is
transcribed by all NK cells (7, 8, 9). In this report, we
show that 2DL4 is an activating receptor with the unique property of
inducing IFN- production but not cytotoxicity in resting NK
cells.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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BALB/c mice were immunized i.p. five times with 5 x 106 NK3.3 cells and boosted once with 50 µg 2DL4-Ig fusion protein. Supernatants of hybridomas produced by fusion with P3x63Ag8 were screened by ELISA with 2DL4-Ig fusion protein (9). Positive hybridomas were further tested by flow cytometry on NK3.3 cells. Three hybridomas were obtained after subcloning: 33 (IgG1), 36 (IgM), and 64 (IgM). The hemaggluttinin (HA)-tag specific Abs (Covance, Richmond, CA) used were mAb 16B12 (IgG1) and polyclonal rabbit Ab HA.11. The mAbs directed against NK surface proteins were 2B4 (C1.7, IgG1; Beckman Coulter, Miami, FL); CD94 (HP3D9, IgG1; Ancell, Bayport MN), and CD16 (3G8, IgG1; Medarex, Princeton, NJ). Isotype-matched control Abs for IgG1, IgG2a, and IgM were obtained from Beckman Coulter. The following NK cell lines were used: NK92 (obtained from H. Klingemann, Rush Unversity, Chicago IL), NK3.3 (obtained from J. Kornbluth, St. Louis University School of Medicine, St. Louis, MO), and NKL (obtained from M. J. Robertson, Indiana University Cancer Research Institute, Indianapolis, IN). 293T/17 and P815 cells were obtained from American Type Culture Collection (Manassas, VA). Human NK cell populations were derived from the PBL of normal donors as previously described (10) using the MACS NK cell isolation kit (Miltenyi Biotec, Auburn, CA). Freshly isolated NK cells cultured in Iscove’s medium containing 10% human serum without any added cytokines were used within 24 h. NK cells were expanded in the presence of IL-2 as previously described (10).
Molecular construct transfections and immunoblotting
The 2DL4 cDNA cloned into pBlueScript was used as a PCR template using the following primers: sense primer (containing a BglII site), 5'-GGGGAGATCTCACGTGGGTGGTCAGGACAA-3'; and antisense primer (containing SalI and NheI sites), 5'-GACTGGTCGACGCTAGCTCAGATTCCAGCTGCTGGTA-3', and cloned into the BglII and SalI sites of pDisplay in frame with a signal sequence and a HA tag (Invitrogen, Carlsbad, CA). To produce the HA-2DL4 (RY-GT) mutant, the pDisplay-HA-2DL4 was mutated using the QuikChange kit (Stratagene, La Jolla, CA). Primers used were: sense, 5'-CATGCTGTGATTGGGACCTCAGTGGCCATC-3'; and antisense, 5'-GATGGCCACTGAGGTCCCAATCACAGCATG-3'. Wild-type and mutant HA-2DL4 were cloned using KpnI and NheI into the vaccinia virus vector pSC65 with a modified polylinker, and recombinant viruses were produced as previously described (9). All constructs were verified by sequencing. The 293 T/17 cells were transiently transfected using LipofectAMINE (Life Technologies). After 48 h, cells were lysed in 0.3% 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate, 20 mM Tris-HCl (pH 7.4), 150 mM NaCl, 1 mM PMSF, and 8 mM iodoacetamide. Samples were either used as total lysate or immunoprecipitated with mAbs followed by protein G-agarose (Life Technologies). Western blotting was done as previously described (10), and blots were developed using rabbit anti-HA Abs (Covance), followed by goat anti-rabbit IgG peroxidase (Amersham, Arlington Heights, IL) and Super Signal substrate (Pierce, Rockford, IL).
Functional assays with NK cells
NK cells (5 x 105/well) were
cocultured with or without P815 cells (1 x
105/well) for 20 h with mAbs as indicated.
Culture supernatants were tested for IFN- production by ELISA (R&D
Systems, Minneapolis, MN). In parallel, NK cells were also tested for
cytotoxicity against P815 cells in a 3-h
51Cr-release assay. Purified vaccinia viruses
were used to infect IL-2-activated NK cells as previously described
(9). After infection with 10 PFU/cell of each virus for
1.5 h, cells were washed and either monitored for receptor
expression by flow cytometry or plated for standard 3-h
51Cr-release assays using P815 target cells.
Treatment of NK cells with the extracellular signal-regulated (ERK)
kinase (MEK)1 inhibitor PD098059 (Calbiochem, La Jolla, CA) or the p38
mitogen-activated protein kinase (MAPK) inhibitor SB203580
(Sigma-Aldrich, St. Louis, MO) was for 1–2 h at 37°C before addition
of Abs or rIL-2 (5 U/ml). Inhibitors were present during stimulation
with mAbs. Negative controls contained as much DMSO as the highest
concentration of inhibitor. The inhibitors did not interfere with NK
cell viability as assessed by trypan blue exclusion. After 20 h,
culture supernatants were tested for IFN- by ELISA.
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Results and Discussion |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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The mAbs against 2DL4 were generated to characterize the
expression and signaling properties of 2DL4. One IgG (#33) and two IgMs
(#36 and #64) were identified that reacted specifically with 2DL4 and
not other KIR family members. In an ELISA, mAb 33 bound to 2DL4-Ig but
not to KIR-Ig fusion proteins of 2DL1, 2DL2, 2DL3, and 3DL2 (Fig. 1
A). This mAb also did not
bind KIR-Ig fusion proteins of 2DS2 and 2DS4 (data not shown). Similar
results were obtained with the mAbs 36 and 64 (data not shown). These
mAbs also reacted with cells transfected with 2DL4 but not 2DL5, a
closely related KIR (C. Chang and A. King, personal
communication).
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B). All three anti-2DL4 mAbs bound to the NK cell line
NK3.3, but not to the B cell line 721.221 and the T cell line Jurkat as
shown by flow cytometry (Fig. 1C and data not shown). The NK
cell lines NKL and NK92 displayed low levels of cell surface 2DL4. NK
cells isolated from peripheral blood of different donors varied from
low (similar to that seen with NK92) to intermediate (as shown in Fig. 1C) reactivity with the different anti-2DL4
mAbs.
The 2DL4-specific mAb 33 was used to test whether 2DL4 induces
activation or inhibition of lysis. Lysis of the FcR-positive P815 cells
by IL-2-activated NK cells in the presence of mAb 33 was comparable to
that obtained with mAbs to the activation receptors 2B4 and CD16 (Fig. 2A). Lysis of P815 cells
induced by mAb 33 was also obtained with several NK cell clones and
with the cell lines NK92, NKL, and NK3.3 (data not shown). We conclude
that 2DL4 has properties of an activation receptor.
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A and data not shown). Thus, the activation signal
delivered by 2DL4 in activated NK cells is typical of NK activation
receptors that are sensitive to inhibition by ITIM-containing
receptors.
Resting NK cells were incubated with P815 cells in the presence of mAbs
for 2DL4, CD16, and 2B4 (Fig. 2B). Enhancement of lysis by
CD16 and by 2B4 was similar to that obtained with activated NK cells,
except for the weaker lytic potential of freshly isolated NK cells. In
contrast, 2DL4 did not enhance cytotoxic activity in resting NK cells.
Thus, 2DL4 induction of killing was restricted to activated NK cells,
distinguishing its activity from that of CD16 and 2B4. Coligation of
2B4 or CD16 with CD94 did not decrease the level of lysis (Fig. 2B and data not shown), even though resting NK populations
were chosen that yielded activated NK cells in which CD94 was
inhibitory. Time course (6–72 h) and titration studies with 0.1–16
µg/ml of the Abs against 2DL4, 2B4, and CD16 were done to ensure that
the unique induction of IFN- but not cytotoxicity upon 2DL4
activation was not a function of the intensity of mAb triggering (data
not shown).
The transmembrane region of 2DL4 is necessary for the activation signal
Recombinant vaccinia viruses encoding 2DL4 and a mutated 2DL4 in
which the amino acids arginine-tyrosine in the transmembrane region
were replaced by the glycine-threonine (mutant RY-GT) conserved in all
other KIR receptors were generated. HA-2DL4 was used to distinguish
recombinant from endogenous 2DL4. Homogenous surface expression of
these receptors was obtained by infection of NK cell populations (Fig. 3A). Ligation of wild-type
HA-2DL4 receptor by anti-HA mAb resulted in activation of lysis of
P815 cells (Fig. 3B). In contrast, ligation of the RY-GT
mutant did not result in activation despite higher expression of mutant
RY-GT than wild-type HA-2DL4 and even though P815 lysis was induced by
ligation of 2B4 in the same infected cells. The small reduction in
lysis of P815 cells as compared with control Abs may be a function of
the inhibitory effect mediated by the ITIM in the cytoplasmic tail.
Mutation of the tyrosine in the ITIM to a phenylalanine did not
diminish the ability of 2DL4 to activate lysis (M. Faure, S.
Rajagopalan, and E. O. Long, unpublished observations). We
conclude that 2DL4-mediated activation requires an intact transmembrane
domain but no ITIM. The unique arginine-tyrosine motif is conserved in
the transmembrane region of 2DL4 in humans, chimpanzees, and rhesus
monkeys (11, 12). It is likely that the arginine in the
transmembrane domain mediates association with a partner chain
responsible for the activation signal, as seen with other NK-activating
receptors that associate with either FcR, DAP12, or DAP10
(4). Transfection experiments in the Ba/F3 and 293T cell
lines have also indicated that 2DL4 does not pair with FcR chain,
DAP12, or DAP10 chains (J. Wu, T. Pertel, and L. Lanier, unpublished
observation). Studies are underway to identify the putative
partner chain of 2DL4.
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production by resting NK cells
IFN- secretion in both activated and resting NK cells was
measured after coculture with P815 cells in the presence of mAbs to NK
receptors. In activated NK cells, the ability of 2DL4 to induce IFN-
was greater than that of the activation receptors CD16 and 2B4 (Fig. 4A). As seen in cytotoxicity
assays (Fig. 2A), coligation of 2DL4 with CD94 resulted in
inhibition of IFN- production (Fig. 4A). Activation of
IFN- production by 2DL4 cross-linking was even more striking in
resting NK cells (Fig. 4B). By comparison, ligation of 2B4
and CD16 induced a much smaller response. Coligation of 2DL4 with CD16
had no additional effect on IFN- secretion (Fig. 4B).
Therefore, in resting NK cells, 2DL4 is unique in its ability to induce
efficient IFN- production in the absence of any discernible lytic
function. Intracellular staining of IFN- in both activated and
resting NK cells stimulated with 2DL4 revealed that expression occurred
in the bulk of the NK cell population (data not shown) in contrast to
the selective expression of IFN- by CD56bright
NK cells in response to IL-12 (13).
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production (Figs. 2 and 4, A). In
contrast, similar co-cross-linking on resting NK cells did not inhibit
IFN- secretion induced by 2DL4 (Fig. 4B) or lysis induced
by 2B4 (Fig. 2B). Expansion of NK cells from this resting NK
population yielded cells with inhibitory CD94 (data not shown). The
lack of 2DL4 sensitivity to CD94-mediated inhibition in resting cells
could be due to different repertoires of CD94/NKG2 on resting vs
activated NK cells. Alternatively, the ITIM-based inhibitory pathway
may not function in resting NK cells. In any case, it is significant
that activation through 2DL4 in resting NK cells is not inhibited by
the receptor for HLA-E.
Robust IFN- production was obtained by incubation with the IgG1 33
or either one of the two IgM mAbs in the absence of further
cross-linking (Fig. 4C). The use of the two IgM mAbs, 36 and
64, excluded a role of FcR in the activation by 2DL4. Therefore, the
signal transduced by 2DL4 alone induces IFN- production by resting
NK cells in the absence of cytokines or signals from other receptors.
In contrast, engaging the receptors CD16 and 2B4 with soluble mAbs is
not sufficient, and additional accessory interactions are needed to
trigger IFN- release (Refs. 10 and 14 and
data not shown).
The IFN- secretion by NK cells induced by IL-2 depends on an ERK
mitogen-activated protein kinase pathway (15). The
ERK-dependent IFN- secretion was also observed upon cross-linking of
CD16 or 
1 integrin on activated NK cells or by
mixing NK cells with the sensitive target cell line K562 (16, 17). Inhibitors of MEK1 (PD98059) and of p38 MAPK (SB203580)
were added to resting NK cells during stimulation with anti-2DL4
mAbs to test whether 2DL4-induced production of IFN- required MAPK
(Fig. 4D, top). Complete inhibition occurred at 1
µM of the p38 inhibitor SB203580. The ERK pathway inhibitor, PD98059,
had only a partial inhibitory effect. In contrast, the IL-2-mediated
induction of IFN- production was severely inhibited by 50 µM
PD98059 and unaffected by SB203580 (Fig. 4D,
bottom), as previously reported (15). Thus, the
p38 MAPK-dependent 2DL4 signal for IFN- secretion is different from
signals delivered to activated NK cells by CD16 and
1 integrin and to resting NK cells by the
IL-2R, which are all sensitive to an ERK MAPK inhibitor. Further
biochemical analysis of the 2DL4 signaling pathway has been hampered
thus far by the limited number of freshly isolated resting NK cells
available. Polarization of cytotoxic granules in NK cells, leading to
target cell killing, is also erk dependent (18). The use
of a p38 rather than an ERK pathway for activation of resting NK cells
by 2DL4 may be designed to avoid cytotoxicity while maintaining the
IFN- response. In this regard, IFN- induction by 2DL4 is similar
to IFN- production by Th1 cells and to IFN- gene transcription in
T cells stimulated by IL-12 and IL-18 that are also regulated by p38
(19, 20).
To fully understand the physiological relevance of 2DL4-mediated
IFN- production, the ligands that recognize this receptor need to be
identified. One ligand that interacts with 2DL4 is HLA-G, because 2DL4
binds to cells expressing HLA-G (8, 9, 21). HLA-G is
expressed by fetal trophoblast cells that invade maternal decidua,
where they encounter NK cells during early pregnancy (22).
Uterine NK cells are a major source of IFN- in pregnant mice, in
which IFN- has an important role in vascularization at the
implantation site (23). We have observed enhanced IFN-
production by resting NK cells in the presence of HLA-G-expressing
cells (S. Rajagopalan and E. O. Long, unpublished observations).
The potential role of 2DL4 in stimulating IFN- production during
pregnancy warrants further study with decidual NK cells and trophoblast
cells.
This study has identified 2DL4 as a receptor with the unique and
autonomous ability to induce rapid IFN- secretion but not
cytotoxicity by resting NK cells in the absence of cytokines. Signals
that can activate resting NK cells have physiological relevance to the
in vivo induction of NK responses. Furthermore, we show that resting NK
cells behave differently than activated NK cells in terms of the
outcomes of receptor activation. This is noteworthy because most
studies on NK receptor function are conducted using IL-2-activated NK
cell populations or clones. The polarized response of resting NK cells
to signals received from 2DL4 vs other activation receptors is
analogous to the distinct NK responses induced by different cytokines
and reveals another facet in the complex regulation of these effector
cells.
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Acknowledgments |
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Footnotes |
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2 Abbreviations used in this paper: KIR, killer cell Ig-like receptor; ITIM, immunoreceptor tyrosine-based inhibition motif; HA, hemagglutinin; ERK, extracellular signal-regulated protein kinase; MAPK, mitogen-activated protein kinase; MEK, erk kinase.
Received for publication May 29, 2001. Accepted for publication June 28, 2001.
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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]
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J. P. Goodridge, C. S. Witt, F. T. Christiansen, and H. S. Warren KIR2DL4 (CD158d) Genotype Influences Expression and Function in NK Cells J. Immunol., August 15, 2003; 171(4): 1768 - 1774. [Abstract] [Full Text] [PDF]
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X. Gu, A. Laouar, J. Wan, M. Daheshia, J. Lieberman, W. M. Yokoyama, H. R. Katz, and N. Manjunath The gp49B1 Inhibitory Receptor Regulates the IFN-{gamma} Responses of T Cells and NK Cells J. Immunol., April 15, 2003; 170(8): 4095 - 4101. [Abstract] [Full Text] [PDF]
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 J. Li, B. A. Rabinovich, R. Hurren, J. Shannon, and R. G. Miller Expression cloning and function of the rat NK activating and inhibitory receptors NKR-P1A and -P1B Int. Immunol., March 1, 2003; 15(3): 411 - 416. [Abstract] [Full Text] [PDF]
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H.-W. Chan, Z. B. Kurago, C. A. Stewart, M. J. Wilson, M. P. Martin, B. E. Mace, M. Carrington, J. Trowsdale, and C. T. Lutz DNA Methylation Maintains Allele-specific KIR Gene Expression in Human Natural Killer Cells J. Exp. Med., January 20, 2003; 197(2): 245 - 255. [Abstract] [Full Text] [PDF]
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 M. D. Cooper, L. L. Lanier, M. E. Conley, and J. M. Puck Immunodeficiency Disorders Hematology, January 1, 2003; 2003(1): 314 - 330. [Abstract] [Full Text] [PDF]
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P. Le Bouteiller, A. Barakonyi, J. Giustiniani, F. Lenfant, A. Marie-Cardine, M. Aguerre-Girr, M. Rabot, I. Hilgert, F. Mami-Chouaib, J. Tabiasco, et al. Engagement of CD160 receptor by HLA-C is a triggering mechanism used by circulating natural killer (NK) cells to mediate cytotoxicity PNAS, December 24, 2002; 99(26): 16963 - 16968. [Abstract] [Full Text] [PDF]
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J. E. Boyson, R. Erskine, M. C. Whitman, M. Chiu, J. M. Lau, L. A. Koopman, M. M. Valter, P. Angelisova, V. Horejsi, and J. L. Strominger Disulfide bond-mediated dimerization of HLA-G on the cell surface PNAS, December 10, 2002; 99(25): 16180 - 16185. [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. S. Farag, T. A. Fehniger, L. Ruggeri, A. Velardi, and M. A. Caligiuri Natural killer cell receptors: new biology and insights into the graft-versus-leukemia effect Blood, August 28, 2002; 100(6): 1935 - 1947. [Abstract] [Full Text] [PDF]
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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]
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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]
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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]
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S. S. Chuang, P. R. Kumaresan, and P. A. Mathew 2B4 (CD244)-Mediated Activation of Cytotoxicity and IFN-{gamma} Release in Human NK Cells Involves Distinct Pathways J. Immunol., December 1, 2001; 167(11): 6210 - 6216. [Abstract] [Full Text] [PDF]
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P. Forte, L. Pazmany, U. B. Matter-Reissmann, G. Stussi, M. K. J. Schneider, and J. D. Seebach HLA-G Inhibits Rolling Adhesion of Activated Human NK Cells on Porcine Endothelial Cells J. Immunol., November 15, 2001; 167(10): 6002 - 6008. [Abstract] [Full Text] [PDF]
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), 2DL3 (
), 3DL1
(
), and 2DL4 (
) were tested for reactivity with mAb 33 in an
ELISA. B, Total cell lysate (-) or
immunoprecipitates (IP) using mAb 33 and DX27 from mock- or
HA-2DL4-transfected 293T/17 cells were blotted with anti-HA.
C, Surface 2DL4 expression of the indicated cell lines
and of NK cells from a normal donor as detected with mAb 33. The thin
lines indicate staining with control Abs.
