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Microbiology and Tumor Biology Center, Karolinska Institute, Stockholm, Sweden
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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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Recent experiments have established that the presence of the MHC class I ligand influences the levels of Ly49 receptor expression in vivo (15, 16, 17, 18, 19). For example, in mice lacking H-2Dd, the ligand for Ly49A, NK cells express high levels of Ly49A, but in mice expressing the ligand, Ly49A expression is down-regulated (15). Low Ly49A levels in the presence of H-2Dd has been explained by ligand-induced posttranscriptional modification of Ly49A expression (6, 20). This modification has important functional consequences for Ly49A-expressing NK cells. NK cells with reduced levels of Ly49A are sensitive to small changes in target cell expression of H-2Dd, while NK cells with high Ly49A expression are not (15, 16). A receptor calibration model suggests that ligand-induced down-modulation of Ly49A makes these NK cells useful in mice expressing H-2Dd (21). Without down-regulation, the Ly49A-expressing NK cells, due to their high Ly49A expression, would be inhibited also by target cells expressing low levels of H-2Dd, and would therefore be useless. Thus, ligand-induced down-regulation of Ly49A could be seen as an adaptive response to the environment, aiming at more efficient recognition of self cells that fail to express normal levels of MHC class I.
In this study, we have asked how H-2Dd regulate Ly49A expression. The starting point was the analysis of Ly49A expression in DL6 mice with spontaneous mosaic expression of an H-2Dd transgene. In DL6 mice, H-2Dd-negative and H-2Dd-positive cells coexist in varying proportions, which are constant within each individual mouse but differ between animals (22). By comparing H-2Dd-positive and -negative NK cells in individual mice, the relative roles for H-2Dd expression on surrounding cells vs on the NK cell itself for Ly49A levels could be analyzed in various situations. Furthermore, by comparing individual DL6 mice carrying different percentages of H-2Dd-expressing cells with each other, the sensitivity of the calibration process to varying numbers of ligand-positive cells in the environment could be analyzed. Finally, in a newly developed adoptive transfer model, we addressed the question whether calibration of Ly49A in vivo could occur in mature cells as a consequence of interactions with a new set of MHC class I ligands.
From an analysis of a large set of DL6 mice with different percentages of H-2Dd-positive cells, we conclude that in vivo: 1) H-2Dd expressed by surrounding cells regulated Ly49A expression levels on H-2Dd-negative as well as on H-2Dd-positive NK cells; 2) cell surface levels of Ly49A may depend on the frequency with which an Ly49A-positive NK cell interacts with a surrounding cell expressing H-2Dd. A markedly different result was seen in vitro. In contrast to the in vivo situation, H-2Dd-expression on surrounding cells was inefficient in controlling the down-regulated levels of Ly49A when DL6 NK cells were activated with IL-2. In this situation, expression of H-2Dd on the individual NK cell was required to prevent up-regulation of Ly49A after activation. Finally, in a set of adoptive transfer experiments, we demonstrate that Ly49A levels is not a fixed characteristic of mature NK cells. As early as 10 h after transfer of H-2Dd-negative, Ly49high, NK cells to H-2Dd-positive recipients, Ly49A levels were strongly down-regulated on transferred NK cells. Taken together, our results suggest distinct roles for H-2Dd on the NK cell itself and in the environment of the NK cell for Ly49A receptor levels. They also show that NK cells can rapidly adjust their cell surface levels of Ly49A in response to changes in the MHC class I expressed by surrounding cells, suggesting that receptor calibration against external ligands may be a continuous process that occurs throughout the life span of the NK cell.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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All mice were kept and bred at the Microbiology and Tumor
Biology Center, Karolinska Institute, Stockholm, Sweden. Mosaic DL6
mice and control DL1 mice have been described previously (22). The
transgene in both DL1 and DL6 mice is a chimeric gene containing the
1/2 domains of H-2Dd coupled to the 3 domain of
H-2Ld. However, in control DL1 mice the transgene is
expressed in all cells of the mouse, whereas in DL6 mice it is
expressed in a mosaic fashion (22). The chimeric
H-2Dd/Ld protein, when expressed in all cells
of the mouse, has an effect on NK cell specificity similar to that of
the entire H-2Dd gene (22). We will therefore, for the sake
of simplicity, use H-2Dd in reference to the
H-2Dd/Ld transgene throughout this report.
Flow cytometry
The mAbs 3-25.4 (anti-1/2 domains of
H-2Dd; FITC conjugated), PK136 (anti-NK1.1;
phycoerythrin (PE3)
conjugated), and A1 (anti-Ly49A; biotinylated) were purchased from
PharMingen, San Diego, CA, and streptavidin-RED670 was purchased from
Life Technologies AB, Täby, Sweden. The percentage of
H-2Dd-positive cells in DL6 mice was determined using FACS
analysis of peripheral blood cells stained with FITC-conjugated mAb
against the 1/2 domains of H-2Dd (3-25.4). To analyze
for expression of NK cell receptors, nonactivated nylon
wool-nonadherent (NWNA) spleen cells, or IL-2-activated spleen cells,
were incubated with biotinylated mAb against Ly49A, washed, and in a
second step incubated with a mixture containing streptavidin-RED670,
3-25.4-FITC, and PK136-PE. Incubations were performed on ice for 30
min, and washes were done in PBS supplemented with 1% FCS. Cells were
analyzed on a FACScan (Becton Dickinson, Mountain View, CA).
Activation of NK cells in vitro
Spleen cells were cultured at 37°C in complete medium (-MEM
containing 10% FCS, 100 U/ml penicillin, 100 µg/ml streptomycin, 10
mM HEPES buffer, and 2 x 10-5 M 2-ME) in the
presence of 1000 U/ml of rIL-2 and in a 10% CO2/90% air
mixture as described (23, 24). After 4 days, both adherent and
nonadherent cells were removed and used for flow cytometry analysis as
described in the previous section. The starting material was either
erythrocyte-depleted spleen cells or separated
H-2Dd-negative DL6 spleen cells.
Cell separation and coculture experiments
Dynabeads conjugated to a rat anti-mouse IgM Ab (M-450;
Dynal, Oslo, Norway) were preincubated with an IgM mAb specific for
H-2Dd 1/2 (34-4-21S) for 30 min at 4°C. A total of
1.5 µg Ab/long beads were used. Erythrocyte-depleted DL6 splenocytes
were incubated with the precoated beads for 30 min at 4°C, and beads
with bound cells were subsequently collected using a magnetic particle
concentrator. The procedure was repeated once to completely deplete the
sample of H-2Dd-positive cells. Incubations and washes were
made in PBS containing 0.1% BSA. After separation,
H-2Dd-negative DL6 cells were cultured either alone or
together with increasing numbers of H-2Dd-positive spleen
cells in rIL-2, and the expression of Ly49A receptor was analyzed 4
days later. For the coculture experiments, we could not use separated
H-2Dd-positive DL6 cells since they were attached to the
beads. Separated H-2Dd-negative DL6 cells were therefore
mixed with increasing numbers of spleen cells from DL1 mice treated
with NK1.1 Ab to deplete NK cells. NK cell depletion was necessary to
prevent DL1 NK cells to kill the H-2Dd-negative cells in
the mixture (our unpublished data).
Adoptive transfer
NWNA spleen cells (15 x 106) were inoculated i.v. into 400-rad-irradiated recipient mice. Recipients were killed 10–18 h later, and splenic NK cells were analyzed by FACS for Ly49A expression.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Cell surface levels of Ly49A were measured on NK cells from B6
mice(noH-2Dd), DL1 mice (H-2Dd expression in
all cells) and on H-2Dd-positive and negative NK cells from
mosaic DL6 mice. Nontransgenic B6 NK cells expressed high cell surface
levels of Ly49A, as previously reported. In contrast,
H-2Dd-negative NK cells in mosaic DL6 mice had
down-regulated Ly49A levels (Fig. 1
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only difference between these two NK cell populations was that
H-2Dd-negative DL6 NK cells had matured in an environment
containing H-2Dd-expressing cells. Thus, interactions with
H-2Dd-expressing cells led to down-regulation of Ly49A
receptor expression on cells that did not express H-2Dd
themselves. Using mixed bone marrow chimeric mice, we confirmed that
the mosaic DL6 mice were not unique in promoting low Ly49A levels on
H-2Dd-negative cells. Down-regulation of Ly49A on
B6-derived NK cells occurred also when B6 and
H-2Dd-expressing bone marrow cells were mixed and allowed
to mature in irradiated H-2Dd-transgenic hosts (data not
shown). Altogether, these data are consistent with previous results
from studies of the regulation of Ly49A expression in long term bone
marrow chimeric mice (25).
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The number of H-2Dd-positive cells in DL6 mice varies
between individual mice but is stable within a given animal (22). To
investigate whether the percentage of H-2Dd-positive cells
in the environment would influence Ly49A levels, we compared NK cells
from several DL6 mice containing different numbers of
H-2Dd-positive cells. When the Ly49A expression from all
mice were plotted against the percent H-2Dd-positive cells
in DL6 mice, we observed a linear correlation
(p < 0.001) between these two parameters.
Down-regulation of Ly49A was less pronounced in mice with a low
percentage of H-2Dd-expressing cells and became more marked
as the percentage of H-2Dd-positive cells increased (Fig. 2). Interestingly, this correlation was
observed for both H-2Dd-positive and negative cells. From
this comparison we draw three conclusions: 1) down-regulation of Ly49A
is an efficient process that occurs in mice in which only 1 cell of 10
expresses H-2Dd; 2) The extent of down-regulation of Ly49A
may depend on the frequency with which an NK cell interacts with a
surrounding cell expressing the ligand; 3) H-2Dd expression
on surrounding cells may determine Ly49A levels even if
H-2Dd is present on the cell surface of the NK cell itself.
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To test whether Ly49A levels could be changed in mature NK cells
when the MHC environment was changed, we separated DL6 spleen cells
into an H-2Dd-positive and an H-2Dd-negative
population and cultured them either separately or together for 4 days
in medium supplemented with IL-2. Under both these culture conditions,
Ly49A expression in the H-2Dd-positive subset only changed
marginally, if at all. In contrast, Ly49A expression increased
dramatically in the H-2Dd-negative population. Since these
changes were observed both in cultures where the mosaic population was
left without separation (Fig. 3A) and in cultures where the
H-2Dd-negative cells were cultured separately (Fig. 3B), we conclude that in the presence of IL-2, the influence
of surrounding cells was minimal. Instead, the MHC ligand of the NK
cell itself acted to maintain low receptor expression. This was also
the case when conditions were pushed such that most of the cells in the
environment were H-2Dd positive. Mosaic DL6 mice with
>50% H-2Dd-positive cells are rare, so this was achieved
by coculturing separated H-2Dd-negative DL6 cells with
increasing numbers of H-2Dd-positive cells. Despite a
ninefold excess of H-2Dd-positive over -negative cells, the
Ly49A levels on H-2Dd-negative NK cells increased after
IL-2-activation (Fig. 3B). This result showed that the
H-2Dd molecules of the NK cell itself acted to maintain
stability of the down-regulated Ly49A expression upon cellular
activation. Without cell surface expression of H-2Dd, Ly49A
expression rapidly rose to levels comparable to those in B6 mice,
despite a large number of H-2Dd-expressing surrounding
cells.
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To test whether Ly49A levels could be down-regulated in mature NK
cells after exposure to surrounding H-2Dd-positive cells,
we mixed H-2Dd-positive and -negative mature spleen cells
and cultured them together in IL-2 in vitro. This attempt failed; Ly49A
expression on B6 NK cells was high from the beginning and remained high
during the coculture (data not shown). We therefore went back to the in
vivo situation, where the influence of surrounding cells seemed
dominant, and asked whether Ly49A levels could be down-regulated in
mature NK cells if they were exposed to a changed MHC class I
environment in vivo. To test this, we developed an adoptive transfer
system, in which mature splenocytes were inoculated into sublethally
irradiated mice of various MHC genotypes. The spleens of recipient mice
were recovered 10–18 h after inoculation, and donor NK cells were
analyzed for Ly49A expression. We first transferred B6 splenocytes to
BALB/c (H-2d) and BALB.B (H-2b) mice, which
differ only with respect to the MHC genotype but share the same non-MHC
background. The advantage of this donor/recipient combination is that
donor-derived NK cells can be positively identified both by their
unique expression of the NK1.1 marker and by the Ly49A allele
recognized by the A1 Ab (Fig. 4A). Eighteen hours after
transfer, injected B6-derived NK cells demonstrated greatly reduced
Ly49A levels in BALB/c recipients (expressing the H-2Dd
ligand) but not in H-2b-expressing BALB.B mice (Fig. 4B). The levels of Ly49A on the donor-derived NK cells in
BALB/c recipients (Fig. 4B) was similar to the levels
expressed by NK cells in DL1 mice (data not shown).
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). Surprisingly, Ly49A levels were lower
in A.Ca mice (H-2f) than in A.By (H-2b) and
A.Sw (H-2s) mice, although still higher than in A/Sn
(H-2a) mice, suggesting that one or several of the MHC
class I molecules expressed in this haplotype may constitute a ligand
for Ly49A. Down-regulation of Ly49A after transfer to A/Sn and A.Ca
mice were both statistically significant relative the A.By recipients
(Fig. 5). We also inoculated B6 spleen cells into
H-2Dd-transgenic B6 mice (D8). B6 and D8 NK cells cannot be
distinguished using the NK1.1 marker, but gating on
H-2Dd-negative cells in the D8 recipient 10 h after
transfer revealed strong down-regulation of Ly49A on the B6-derived NK
cells (data not shown). Together, these findings show that rapid
down-regulation of Ly49A can take place in mature
H-2Dd-negative NK cells when the environment changes with
respect to MHC class I expression.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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However, with the mosaic DL6 mice, we were able to ask further questions. The first was whether the number of H-2Dd-positive cells in the environment affected the final level of Ly49A. This analysis was possible because individual DL6 mice have different percentages of H-2Dd-positive cells (22). When data from a large cohort of DL6 mice were pooled, we found a highly significant inverse correlation between the number of H-2Dd-positive cells in the mouse and the Ly49A levels, suggesting that Ly49A levels may be determined by the frequency by which an NK cell encounters an H-2Dd-expressing cell. An interesting possibility is that this correlation reflects a calibration process dependent on continuous contacts with H-2Dd-positive cells in vivo. In mice in which H-2Dd-positive cells are rare, such as in DL6 mice with few H-2Dd-expressing cells, the frequency by which an Ly49A-positive NK cell interacts with an H-2Dd-positive cell is likely reduced. Thus, the time elapsing between two H-2Dd contacts would in this case be long enough to allow Ly49A protein to accumulate to higher levels at the cell surface of NK cells. This hypothesis remains to be tested, but it fits with the suggestion that Ly49A receptor levels are regulated by a posttranscriptional event, triggered after contact with H-2Dd-expressing cells (6, 20). It is also consistent with our data from the adoptive transfer experiments in this report, which show that the Ly49A levels on mature NK cells rapidly change after contact with H-2Dd-positive cells in vivo (see below). Our study is not the first to describe a quantitative relationship between the amount of H-2Dd in the environment and Ly49A expression. Using bone marrow chimeric mice, Sykes et al. (25) reported that the Ly49A level on donor cells was down-regulated to a larger extent in recipient mice homozygous for the H-2Dd-gene than in recipients heterozygous for H-2Dd. This result indicated that the level of H-2Dd expressed by individual calibrating cells in the environment was an important factor for the extent of Ly49A down-regulation. These results are not mutually exclusive with the results in this report, which imply the number of surrounding H-2Dd-positive cells as a critical factor. The overall strength of the Ly49A/H-2Dd interaction is likely affected both by the level of H-2Dd on individual cells (as in the study by Sykes et al.) and by the frequency of encounters with H-2Dd-positive cells (our study). Alterations in either parameter would thus be expected to affect Ly49A levels.
The second question in which DL6 mice were useful related to the role of the MHC class I of the NK cell itself. Since H-2Dd-positive and -negative NK cells coexist in the same environment in DL6 mice, we reasoned that a comparison between these two NK cell populations would reveal differences in Ly49A expression in situations where the MHC class I of the NK cell itself was important and no difference when it was not. As has already been discussed, higher Ly49A levels were found on both the H-2Dd-positive and -negative NK cell populations in DL6 mice with a low percentage of H-2Dd-expressing cells than in mice with a high percentage. This result suggests that calibration in vivo may be exclusively dependent on contacts with H-2Dd expressed by cells in the environment, even if the NK cell itself expresses H-2Dd. However, in contrast to the in vivo situation, a difference between H-2Dd-positive and negative NK cells were found in vitro, in response to activation with IL-2. High doses of this cytokine activates NK cells and leads to the development of MHC class I-specific killing responses (23, 24). We found that the low Ly49A levels on H-2Dd-negative DL6 NK cells (down-regulated by H-2Dd on surrounding cells) were highly unstable, and Ly49A expression rapidly rose to high levels after activation in IL-2. In contrast, if the NK cell itself expressed H-2Dd, Ly49A levels remained low during activation. Thus, in this case, H-2Dd on the NK cells were necessary to maintain low Ly49A levels, and H-2Dd molecules expressed by surrounding cells were unable to influence Ly49A expression.
This result is interesting in relation to the "missing self" hypothesis, which proposes a role of Ly49 receptors in NK cell detection of self cells with down-regulated levels of MHC class I (7). It has been demonstrated that the levels of Ly49A receptors influence the outcome of an interaction between an Ly49A-positive NK cell and an H-2Dd-positive target cell. If the NK cell is Ly49Ahigh, it can be more easily inhibited than if it is Ly49Alow (15, 16). Thus, mechanisms should exist that prevent the apparently unstable Ly49A receptor expression from increasing upon activation. Our results suggest that expression of MHC class I on the NK cell itself may be one such mechanism, possibly through an interaction with Ly49A at the cell surface. Such an interaction should be possible to identify with biochemical methods. A similar effect of the MHC class I of the NK cell itself on another inhibitory receptor, Ly49C, has recently been observed by Andersson et al.,(30) suggesting that this phenomenon is not unique for Ly49A.
In adoptive transfer experiments, we found that down-regulation of Ly49A in H-2Dd-negative NK cells occurred rapidly when they were transferred to H-2Dd-expressing mice. This down-regulation was specific since it did not occur in mice of the H-2s or H-2b haplotypes (26). Interestingly, in addition to H-2Dd, a weak, but statistically significant, down-regulation was seen in H-2f mice, suggesting that any one of the MHC class I molecules expressed in this haplotype may constitute a ligand for Ly49A, perhaps with lower affinity. The extent of down-regulation in H-2f mice parallels the down-regulation we have previously observed in mice expressing an H-2Dp transgene (our unpublished data). This may be significant in light of the data showing that H-2d, H-2f, and H-2p share a genetic determinants governing the specificity of NK cell-mediated rejection of bone marrow grafts (27, 28, 29).
The rapid down-regulation of Ly49A after transfer demonstrates that Ly49A down-regulation does not require normal NK cell maturation. More importantly, it also suggests that Ly49A levels on mature NK cells are not fixed but can be influenced in mature cells after interactions with surrounding cells. If this is true, it may have important implications for NK cell function. The "missing self" model suggests that NK cells react against cells with down-regulated MHC class I expression (7). If this hypothesis is correct, each NK cell must express a level of inhibitory receptors that makes it capable of distinguishing small changes in self MHC class I expression, the most important consideration being that receptor levels on individual NK cells are not too high. Given the rapid adaptation in Ly49A levels that was seen against surrounding cells, we speculate that a continuous calibration against surrounding cells could occur in vivo, serving to optimize the NK cell to varying levels of MHC class I molecules expressed in different tissue compartments, thereby adapting it to detect small changes in MHC class I expression in each compartment. Such a mechanism may also be dangerous, since an NK cell continuously calibrating its levels of inhibitory receptors against the environment would run the risk of being tolerized, rather than activated, by pathologic changes in MHC class I ligand expression. However, this would not occur if calibration switches to internal ligands (the MHC class I of the NK cell itself) under conditions of strong activation, as shown by the data in this study. Further studies should reveal whether, in addition to IL-2, other inflammatory cytokines, and perhaps also cell-bound ligands, may release the NK cell from the continuous adaptation of receptor levels to external ligands. At this stage, we conclude that expression of Ly49A receptors is subject to calibration in the mature NK cell according to principles in which the influence of external and internal MHC class I ligands appear to be balanced differentially depending on the cellular activation stage.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Petter Höglund, Microbiology and Tumor Biology Center, Karolinska Institute, Box 280, S-171 77 Stockholm, Sweden. E-mail address:
3 Abbreviations used in this paper: PE, phycoerythrin; NWNA, nylon wool nonadherent.
Received for publication May 12, 1998. Accepted for publication August 7, 1998.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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