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Howard Hughes Medical Institute and Division of Rheumatology, Department of Medicine and Pathology, Washington University School of Medicine, St. Louis, MO 63110
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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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Whereas CD94/NKG2A orthologs are clearly present in both species (3, 4, 5), it is not yet clear whether true orthologs of mouse Ly-49 and human KIR exist in the reciprocal species. Although an incomplete human Ly49 has been isolated (6), functional human Ly-49 molecules have yet to be described. On the other hand, the first recognized mouse NK cell receptor with structural homology to human KIR was the ITIM-containing gp49B receptor, originally identified on mouse mast cells (7), but also expressed by IL-2-activated NK (LAK) cells (8, 9, 10). gp49B has since been shown to inhibit cellular activation by a mechanism involving SHP-1 (11, 12). While gp49B contains ITIMs, another related family member (gp49A) has a much shorter cytoplasmic domain lacking ITIMs or any other tyrosine-based signaling motifs (13). Despite the predicted functional difference between gp49A and B, they are highly conserved in their extracellular domain, displaying 89% amino acid identity. As such, gp49A and B resemble human KIRs that have ITIM-less noninhibitory forms, the so-called killer activation receptors. Despite these similarities to human KIR, mouse gp49 expression is not restricted to NK cells, and in fact, gp49 was first thought to be mast cell specific. Furthermore, gp49A does not contain transmembrane-charged residues that are characteristic of ITIM-less killer activation receptor molecules. These differences suggest that mouse gp49 molecules are not true orthologs of human KIR.
Although the function of gp49A is not known, it is clear that gp49B can
inhibit cellular activation pathways. When co-cross-linked with
Fc
RI, gp49B inhibits granule release from bone marrow-derived mast
cells (14). The function of native gp49B on NK cells has
not been reported, although a chimeric receptor containing the gp49B
cytoplasmic tail could impair NK cell cytolytic function
(9). While these data suggest that gp49B plays an
important regulatory function on NK cells, the cellular distribution of
the gp49 receptors on primary hemopoietic cells is not known because
all of the published studies have examined mast cells and NK cells that
have been cultured in vitro with cytokines. In the present study, we
utilize a novel anti-gp49 Ab to further characterize the gp49
receptors. Unexpectedly, we failed to detect gp49 expression on naive
splenic and liver-derived NK cells. Instead, only cells of the myeloid
lineage constitutively express gp49. Although unstimulated NK cells are
devoid of gp49, NK cells stimulated in vitro by IL-2 express gp49,
including the inhibitory form, gp49B. Most importantly, gp49 expression
is also induced on NK cells upon in vivo murine CMV infection,
suggesting an important physiological role for gp49 receptors in
regulating NK cell activity following viral infection.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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C57BL/6, C57BL/6 (IFN-
-/-), and
C57BL/6 (IL-12ß-/-) mice were purchased from
The Jackson Laboratory (Bar Harbor, ME) and housed under specific
pathogen-free conditions at Washington University. Mice were analyzed
between the ages of 10 and 16 wk. For mouse infections, 5 x
104 or 7.5 x 104 PFU
of MCMV in complete RPMI were administered by i.p. injection.
Cell lines and Abs
The murine NK cell clone KY-2 (15) was maintained
in complete RPMI 1640 containing 10% FCS (Harlan, Indianapolis, IN),
300 µg/ml L-glutamine, 100 U/ml penicillin, and 100
µg/ml streptomycin, and supplemented with 100 U/ml rIL-2 (Chiron,
Emeryville, CA). CHO cells (dhfr-) were grown in
complete F12 media, and P815 cells were passaged in complete RPMI. CHO
+ gp49 was obtained using Lipofectamine (Life Technologies, Rockville,
MD)-facilitated stable transfection of CHO, with full-length gp49B cDNA
in a dhfr-expressing vector pHßap-r-1neo (35). Clones were selected
based on ability to grow in 
-MEM (no nucleosides), and expression
was amplified by selection in 5 µM methotrexate (Sigma, St. Louis,
MO). P815 and P815 + gp49A (14) were generous gifts from
H. Katz (Harvard Medical School, Boston, MA). For the production of mAb
H1.1, Armenian hamsters were immunized i.p. with 100 µg of gp49B-Fc
(11) in Ribi adjuvant (RIBI ImmunoChem Research, Hamilton,
MT) at 0, 4, 8, and 13 wk and boosted with 50 µg of gp49B-Fc 4 days
before fusion. B cell hybridomas were produced by the Washington
University Hybridoma Center and screened for anti-gp49B activity by
ELISA. Candidate hybridomas were reactive with gp49B-Fc, but not Fc,
and were cloned by limiting dilution. Two hybridomas met this
criterion, and mAb H1.1 was selected for further analysis. mAb H1.1 was
purified from cell-free culture supernatants by protein G-Sepharose
chromatography and was labeled with normal human serum biotin (Pierce,
Rockford, IL) or FITC (Calbiochem, San Diego, CA). The following Abs
were purchased from PharMingen (San Diego, CA) and used for flow
cytometry: PK136 PE (NK1.1), 2C11 PE (CD3), M1/70 PE (Mac-1), RB6-8C5
PE (Gr-1), 1D3 PE (CD19), and H1.2F3 FITC (CD69). Other Abs used
included anti-gp49B (300–314) rabbit antiserum (11),
and mAb B23.1 (16). Hamster IgG isotype control was
obtained from Cappel (Cochranville, PA).
Cell purification
LAK cells were prepared as previously described (17). For RT-PCR analysis, NK1.1+ cells were isolated from the spleens of unprimed mice or from MCMV-infected mice on day 2 postinfection by cell sorting. Sorted cells were greater than 90% NK1.1+. Liver-derived lymphocytes were isolated by teasing cells into suspension and harvested from the interface of a 30% Percoll gradient (Sigma).
Flow cytometry
Cells were incubated with saturating concentrations of primary Ab(s) for 30 min. All Abs used were directly labeled with fluorochrome, except mAb B23.1. After two washes, cells treated with B23.1 were incubated with goat F(ab')2 anti-mouse IgG FITC (Cappel) for 30 min. Cells were analyzed on a FACScan (Becton Dickinson, Sunnyvale, CA), and dead cells were excluded by propidium iodide staining. Depicted is the log of the mean fluorescence intensity staining by the indicated Ab.
mAb-mediated co-cross-linking and cytokine assays
A total of 20 µg/ml of streptavidin (Sigma) was immobilized on
an Immulon 2 96-well plate (Dynex Technologies, Chantilly, VA). Wells
were blocked with 2% BSA/PBS, followed by addition of the activating
anti-NK1.1 Ab PK136 biotin (PharMingen). Where indicated, mAb H1.1
biotin or isotype control mAb 2C11 biotin (PharMingen) were also added.
After three washes, individual wells were incubated with 2 x
105 KY-2 cells in complete RPMI (no IL-2) for
5 h, followed by harvest of cell-free supernatants. GM-CSF and
IFN- levels were assayed by ELISA with cytokine minikits (Endogen,
Woburn, MA) and extrapolated to a standard curve constructed with known
cytokine concentrations.
RT-PCR analysis
Cells from the indicated tissue were homogenized, followed by RBC lysis in hypotonic lysis buffer. Total RNA was prepared using Ultraspec (Biotecx, Houston, TX), from which first strand cDNA was synthesized using Superscript II (Life Technologies). PCR was performed in a Perkin-Elmer 9600 (Norwalk, CT) for 35 cycles (22 s at 94°C, 22 s at 56°C, 30 s at 72°C) using the following primers: HPRT, 5' (404–426)-GTAATGATCAGTCAACGGGGGAC; HPRT, 3' (580–557)-CCAGCAAGCTTGCAACCTTAACCA; gp49A, 5' (280–303)-AGACCAAGTTCAAAATTCGATTT; gp49A, 3' (857–833)-GCATTAGCCTTATTTTTGTGACGAC; gp49B, 5' (260–282)-AGGCCAAGTTCAACATTCCAAGC; and gp49B, 3' (836–812)-GCATTAGCCTTCTTTTTGTGCCCAT.
Specificity of the gp49A and gp49B primers was established using an alternatively spliced gp49A cDNA, missing nucleotides 397–496, and full-length gp49B cDNA. PCR products were analyzed on a 1.2% agarose gel.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The gp49 receptor was originally defined by its reactivity with
the B23.1 rat IgM mAb, which was, in our hands, produced by an unstable
hybridoma (data not shown). To produce a stable hybridoma producing a
high affinity anti-gp49B IgG mAb, we immunized Armenian hamsters
with a gp49B-Fc fusion protein (11) that is reactive with
mAb B23.1 (data not shown). Clone H1.1 was selected based on its
specific reactivity with cells expressing transfected gp49B (Fig. 1
A). Further demonstrating its
specificity, H1.1 immunoprecipitated a 
55-kDa protein that is
recognized in Western blot by a gp49B-specific anti-peptide Ab
(data not shown) (11). In addition to its recognition of
gp49B, mAb H1.1 cross-reacts with gp49A (Fig. 1A), as
determined by flow-cytometric data of gp49A-transfected P815 cells.
This was not unexpected given the high level of similarity between the
extracellular domains of gp49A and B. Surprisingly, however, in
contrast to previous published data (14), the B23.1 mAb
also recognizes gp49A (Fig. 1A). Finally, mAb H1.1 stains
untransfected LAK cells and the NK cell clone, KY-2 (15)
(Fig. 1B), both of which express gp49B transcripts
(8). Thus, mAb H1.1 recognizes native gp49 molecules,
permitting further analysis of the expression and function of the gp49
receptors.
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Whereas gp49 is expressed on in vitro cultivated bone marrow- or
serosal-derived mast cells (18) and LAK cells (8, 9), little is known about gp49 expression on naive cells of
hemopoietic origin. We used flow cytometry to more closely examine the
cellular distribution of gp49 using fluorochrome-labeled mAb H1.1.
Approximately 60% of bone marrow cells from C57BL/6 mice stained with
mAb H1.1 (Fig. 2). A similar proportion
of cells from BALB/c-derived bone marrow was also mAb H1.1 positive
(data not shown), consistent with the observation that gp49 is not
polymorphic (8, 10, 13). The majority of the mAb
H1.1+ cells also expressed high levels of Mac-1
and Gr-1, placing them in the myeloid lineage. Of the bone marrow
lymphoid precursors in C57BL/6, a minor subpopulation of
NK1.1+ cells bound to H1.1, while
CD19+ B cells and CD3+ T
cells did not express gp49. Similar results were obtained from day 14
and day 17 fetal liver, in which gp49 expression was limited to cells
bearing Mac-1 and Gr-1 (data not shown). These data indicate that gp49
is constitutively expressed on most cells of the myeloid lineage from
bone marrow and fetal liver and only on a fraction of bone
marrow-resident NK1.1+ cells.
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) and liver-derived lymphocytes (data not shown)
were also tested for mAb H1.1 staining. In contrast to bone marrow
cells, gp49 was not expressed on NK1.1+ cells
from spleen or liver. CD19+ B cells and
CD3+ T cells also lacked gp49 expression.
Instead, similar to the bone marrow, only Mac-1+
and Gr-1+ cells bound to mAb H1.1. These data
establish that in contrast to LAK cells, naive mouse NK cells fail to
express the gp49 receptor. Activation-induced expression of gp49 on NK cells
Our previous immunofluorescence studies indicated that gp49B is expressed on NK1.1+ cells cultured for 7 days with IL-2 (8). We confirmed this analysis using mAb H1.1 and additionally found that gp49 is inducibly expressed on splenic NK1.1+ cells as early as 2 days after culture in IL-2 (data not shown). Consistent with our previous results, expression of gp49 on NK cells was maintained through day 7 of the IL-2 culture. Inasmuch as gp49 is not expressed on resting splenic NK cells, but is expressed on activated NK cells, these data suggest that NK cell expression of gp49 is induced by cellular activation.
We therefore extended this analysis to in vivo stimulation of NK cells
by examining NK cells from mice challenged with MCMV, which is known to
elicit an immediate NK cell response in C57BL/6 mice (19, 20). C57BL/6 mice were infected with a sublethal dose of MCMV
and, at various time points after infection, cells from the bone
marrow, spleen, and liver were examined by flow cytometry (Fig. 3A). In contrast to naive
mice, gp49 was induced on splenic NK cells by day 2 postinfection and
stayed at high levels on NK cells through day 3 before waning on days 4
and 5 (Fig. 3, A and B). Interestingly, the vast
majority of NK1.1+ cells inducibly expressed
gp49. Similar results were obtained in the liver, in which NK cell
expression of gp49 peaked by days 2 and 3 postinfection. However, the
attenuation of gp49 expression, which occurs rapidly on splenic NK
cells, is slightly delayed on liver NK1.1+ cells,
which express intermediate levels of gp49, 5 days postinfection (Fig. 3B). The expression of gp49 on myeloid cells, T cells, and B
cells from spleen, liver, and bone marrow was unchanged following
infection (data not shown). Mac-1/Gr-1-positive cells constitutively
expressed high levels of gp49, and this remained unchanged through day
5 postinfection. Meanwhile, T and B cells consistently lacked cell
surface gp49. These results suggest that gp49 may be an important
modulator of NK cell function following activation.
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A) with similar
kinetics (Fig. 3B). However, CD69 is inducibly expressed on
a large population of T and B cells, while these cells fail to turn on
gp49 expression. Thus, the induced expression of gp49 differs from that
of CD69. Cytokine involvement in gp49 induction
We next addressed the mechanism of gp49 induction. IL-12 and
IFN- are potent stimuli of NK cells, and both are expressed during
MCMV (21). We therefore examined whether the inducible
expression of gp49 and CD69 by NK cells is IL-12 or IFN- dependent.
IL-12-deficient mice were challenged with MCMV, and liver and splenic
NK cells were analyzed by flow cytometry (Fig. 4). NK1.1+ cells
from infected IL-12-deficient mice expressed comparable levels of gp49
and CD69 as NK cells from MCMV-infected wild-type mice. Similar data
were obtained from IFN- null mice (Fig. 4), indicating that
the inducible expression of gp49 and CD69 on NK cells is not dependent
on either IL-12 or IFN-, two cytokines whose production is
stimulated during MCMV infection.
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As stated previously, mAb H1.1 recognizes both known gp49 family
members, the ITIM-less gp49A and ITIM-containing gp49B, raising the
possibility that either or both are induced following MCMV infection.
We used RT-PCR to examine the distribution of the gp49 family members.
Primers specific for the A or B form of gp49 were used to amplify cDNA
derived from various cell types. cDNA from thymocytes and splenic
NK1.1+ (NK) cells contained low to undetectable
levels of gp49A and B message (Fig. 5),
consistent with our immunofluorescence data. Bone marrow, KY-2, and LAK
cells, on the other hand, expressed both forms of gp49 at comparable
levels. Although we failed to detect gp49 transcripts in splenic
NK1.1+ cells from unchallenged mice,
NK1.1+ cells isolated from MCMV-infected mice
expressed both gp49A and gp49B. Semiquantitative PCR revealed that both
receptors were expressed at comparable levels (data not shown). The
significance of gp49A expression is unclear because its function is not
known. Nevertheless, our data indicate that in vitro and in vivo
expression of an inhibitory receptor, gp49B, on mouse NK cells is
regulated by the activation status of the cell.
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Because the function of gp49 on NK cells has not been directly
tested, we used mAb H1.1 to examine the inhibitory capacity of gp49B on
KY-2 cells, known to express high levels of gp49B (11).
These cells were preferred for this analysis because of the difficulty
in purifying sufficient numbers of NK cells from MCMV-infected spleens.
We and others have observed a precipitous drop in the percentage of NK
cells in the spleen following infection with MCMV (22) (A.
Dokun and W. Yokoyama, manuscript in preparation). KY-2 cells,
following stimulation with biotinylated anti-NK1.1 bound to
immobilized avidin, produce the cytokines GM-CSF (Fig. 6) and IFN- (data not shown). However,
co-cross-linking of the NK1.1 receptor along with gp49B led to
dose-dependent diminution of GM-CSF as well as IFN- release. In
contrast, an isotype control hamster mAb, 2C11, which does not bind to
KY-2 cells (15), exerted minimal effects on cytokine
production. Because NK cells are a potent source of cytokines in the
innate immune response, these data imply that gp49B plays an important
role in shaping early immune responses.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Despite that gp49 is not found on naive NK cells, it is induced on NK
cells following in vitro and in vivo stimulation. This induced
expression is found in NK cell responses to MCMV infection, a notable
observation because of the critical role of NK cells in controlling
lethality and replication by MCMV (19, 20, 23). Although
the mechanism for induction of gp49 expression was not revealed in our
studies, NK cells from MCMV-infected IL-12 or IFN--deficient mice
were fully capable of gp49 expression. This does not exclude a role for
IL-12 or IFN-, but does suggest that neither is required for this
process. Although CD69 is also induced on T and B cells, whereas gp49
is not, CD69 is another NK cell activation-induced receptor with
kinetics of expression that is strikingly similar to gp49 induction.
Therefore, the molecular events underlying gp49 induction are likely to
be somewhat distinct from those involved in CD69 up-regulation.
Although both gp49A and gp49B are induced by NK cell activation, the role of these receptors in MCMV infection, particularly that of gp49B, can be best understood in the context of the large amount of data concerning the better characterized inhibitory receptors on NK cells. The inducible expression of gp49B contrasts with the constitutive expression of Ly-49 receptors on overlapping subsets of naive NK cells, LAK cells, and NK cells from MCMV-infected mice. However, certain Ly-49+ NK cell subsets in the spleen appear to be expanded during MCMV infection (22) (A. Dokun and W. Yokoyama, manuscript in preparation), perhaps by redistribution of these subsets or selective outgrowth. Instead, the inducible expression of gp49 appears to be a general response to NK cell activation, because all NK cells early in the course of Listeria monocytogenes infection, another pathogen that involves an NK cell response (24), also inducibly express gp49 (L. Wang and W. Yokoyama, unpublished observations). Additionally, treatment of mice with poly(I:C) stimulates gp49 expression by NK cells (data not shown). Based on our in vitro observation that stimulation of mature NK cells induces gp49, this enhanced expression of gp49 following MCMV infection is very unlikely due to the recruitment of the small number of gp49+ cells in the bone marrow to the periphery or other redistribution phenomena. These data strongly suggest that gp49 expression is induced upon physiological stimuli and that the role of these receptors is to modulate NK cell activity some time after initial activation. This can be differentiated from the role of Ly-49 and other MHC class I inhibitory receptors that are currently conceived to be constitutively and stably expressed on individual NK cells once the mature repertoire is established (25, 26). Perhaps the constitutive and stable expression of such receptors is not surprising because these MHC class I-specific receptors must act immediately to control untoward NK cell activation. Although the ligands for the gp49 receptors are not yet understood, ongoing studies do not clearly implicate MHC class I ligands (L. Wang and W. Yokoyama, unpublished data). Hence, gp49 receptors and their ligands may play critical roles in returning the activated NK cell population back to resting state, thus playing a potentially important role in NK cell homeostasis.
Whereas gp49B is a functional receptor for inhibition, the function of
gp49A is not yet understood, even though it is clearly not an
inhibitory receptor due to the absence of cytoplasmic ITIMs. On the
other hand, it does not contain a charged transmembrane residue
required for association with signaling chains expressed by NK cells,
such as DAP12, DAP10, FcRI, or CD3
. Furthermore, gp49A does
not contain any tyrosine-based cytoplasmic signaling motifs involved in
cellular activation. Regardless, the induced expression of gp49A may
provide a clue to its physiological function, and this induced
expression may be relevant to a large family of related receptors.
Although there are other examples of NK and TCRs that are induced by
cytokines (27, 28), such studies were limited to in vitro
analysis and did not examine NK cells in virally challenged hosts. In
addition to human KIR molecules, mouse gp49 molecules display
structural homology with mouse paired Ig-like receptor (PIR) (29, 30) and human ILT/LIR receptors, although only a few of these
receptors have been found on NK cells. PIRs are found on cells of the
myeloid lineage, but are also expressed on B cells (31),
unlike gp49. The recently identified human ILT/LIR receptors (32, 33) may represent functional orthologs of mouse gp49. There are
now at least nine known ILT/LIR family members that display
heterogeneous tissue distribution. A few members such as ILT1 (LIR-7)
and ILT2 (LIR-1) can be found on NK cells, but also display tropism for
cells of the myeloid lineage. ILT2 (LIR-1) is also found on B cells and
T cell subsets. Like the gp49 family, there exist ITIM-less ILT/LIR
molecules. Unlike gp49A, one such receptor, ILT1 (34),
through a charged residue in its transmembrane domain, can pair with
FcR and mediate activation of monocytes. Thus, it is not yet
clear how gp49 relates to these otherwise homologous receptors.
Nevertheless, our data also imply that it is worth considering if any member of the growing family of Ig-like receptors may have important functions on not only resting cells, but also on activated cells. A number of these receptors may be induced upon cellular activation on not only NK cells, but also other hemopoietic cells. Such findings would also strongly suggest that the physiological functions of these receptors may be important as regulators of cellular activation, long after the cells are first stimulated, rather than at the time of initial activation, as currently envisioned.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Wayne M. Yokoyama, Rheumatology Division, Box 8045, Department of Medicine, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110.
3 Abbreviations used in this paper: KIR, killer inhibitory receptor; CHO, Chinese hamster ovary; HPRT, hypoxanthine phosphoribosyltransferase; ILT, Ig-like transcript; ITIM, immunoreceptor tyrosine-based inhibitory motif; LAK, IL-2-activated NK cell; LIR, leukocyte Ig-like receptor; MCMV, murine CMV; SHP, src-homology-2 phosphatase-1.
Received for publication December 13, 1999. Accepted for publication March 8, 2000.
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References |
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ß, and TNF effects on antiviral state and NK cell responses during murine cytomegalovirus infection. J. Immunol. 156:4746.[Abstract]
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H. Nakajima, A. Asai, A. Okada, L. Ping, F. Hamajima, T. Sata, and K. Isobe Transcriptional Regulation of ILT Family Receptors J. Immunol., December 15, 2003; 171(12): 6611 - 6620. [Abstract] [Full Text] [PDF]
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