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Department of Immunology, Faculty of Medicine, Imperial College of Science, Technology and Medicine, London, United Kingdom
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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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2-microglobulin,
and an 8–11 aa-long peptide bound in the groove formed by the
N-terminal domains of the H chain (1, 2). The peptides are
generated from endogenous self proteins, or from pathogen-derived
proteins, and their presentation for possible recognition by the TCR of
CD8+ CTL allows immune surveillance of all cells
that express MHC class I (3, 4, 5, 6). MHC class I molecules are
also recognized by other types of signaling receptors in addition to
the TCR. These include receptors on NK cells, which deliver inhibitory
signals such that cells with a normal pattern and level of MHC class I
expression do not activate NK cells (7), and Ig-like
transcripts (8), which are expressed on a wide
range of cells. It is becoming increasingly apparent that MHC class I
molecules signal the condition of a cell to a variety of other cell
types, of which CTL are but one example. Therefore, the precise levels
and nature of MHC class I molecules expressed at the cell surface could
be very important, even in the absence of infection
(9, 10, 11, 12).
MHC class I molecules are encoded by the H-2K, -D
and -L loci on chromosome 17 in the mouse, and by the
HLA-A, -B, and -C loci on chromosome 6
in humans (13), and all of these loci are polymorphic. MHC
class I molecules have been reported to have different intrinsic
properties in terms of association with
2-microglobulin (14, 15), rate of
trafficking (16, 17), molecular interactions with
components of the Ag presentation pathway (18, 19, 20, 21, 22, 23), and
rate of turnover (24). Even though cells may express up to
six different alleles, it has generally been assumed in Ag presentation
experiments that MHC class I alleles function independently of each
other within cells. Two types of observations made many years ago have
suggested that this may not always be the case. Firstly, a variation in
the level of cell surface expression of particular MHC class I alleles
depending on the presence or absence of other alleles has been reported
by two groups looking at expression levels of murine MHC class I
molecules in the spleen (25, 26). Secondly, there is
strong evidence from mouse experiments that the presence of a
particular MHC class I molecule can profoundly influence a CTL response
restricted by another class I molecule (27, 28, 29, 30, 31). For
example, H-2Db-restricted CTL responses to
several different viruses were reported to be severely reduced when the
H-2Kk class I molecule was also present, either
in F1 hybrid or recombinant strains of mice
(28, 29, 30). The mechanism for this type of immunodomination
is not clear, but a recent study using contemporary methods for
analyzing CD8+ T cell responses has confirmed
that the relative prevalence of a particular epitope-specific
population may be influenced by the background MHC molecules
present in the host (32). The aim of this study was to
test the hypothesis that certain MHC class I molecules compete with
each other for cell surface expression, and to test whether such
competition is linked with MHC-related alteration of CTL responses.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Female C57BL/6 (B6), CBA/Ca (CBA), BALB/c, and (B6 x BALB/c), (B6 x CBA), (BALB/c x CBA)F1 hybrid mice were obtained from Harlan Olac (Bicester, U.K.). Male CBA and (B6 x CBA)F1 hybrid mice were obtained from Prof. E. Simpson (Imperial College, London U.K.). H-2Kb-transgenic CBA/Ca mice (CBK) have been described previously (33, 34) and, together with control CBA/Ca mice, were obtained from Prof. H. Waldmann (University of Oxford, Oxford, U.K.).
Infection of mice with influenza virus
Influenza virus A/PR/8/34 (H1N1, Mount Sinai strain) was grown in the allantoic sacs of 11-day-old embryonated chicken eggs and used as infectious allantoic fluid. Dilutions of allantoic fluid were assayed for virus by agglutination of sheep RBC. Eight- to 12-wk-old mice were either anesthetized and infected intranasally (i.n.)3 with 0.01 hemagglutination units of virus in 50 µl PBS, or injected i.p. with 300 hemagglutination units of virus in 500 µl PBS. The low dose of virus used for the natural route of infection (i.n.) was because of the high virulence of the A/PR/8/34 strain of influenza virus in mice. Little or no virus replication takes place after i.p. injection of virus.
Peptides
The influenza A/PR/8/34 virus-derived peptide epitopes used in this study, Db-restricted nucleoprotein ASNENMETM (NP366–374) and polymerase 2 SSLENFRAYV (PA224–233), Kk-restricted nonstructural protein EEGAIVGEI (NS1152–160), hemagglutinin FEANGNLI (HA259–266) and IEGGWTGMI (HA354–362), nucleoprotein SDYGERLI (NP50–57), Dk-restricted polymerase 1 ARLGKGYMF (PB1349–357), and Kb-restricted SSYRRPVGI (PB1703–711) have all been described previously (35, 36, 37, 38, 39, 40, 41) and were supplied by Research Genetics (Huntsville, AL).
ELISPOT assay
Eight days after inoculation with influenza virus, the number of
IFN-
-producing cells in the spleen cell populations from individual
mice was determined by ELISPOT assay, as previously described
(42). Briefly, nitrocellulose-bottomed 96-well plates
(Millipore, Bedford, MA) were coated for 2 h at 37°C followed by
overnight incubation at 4°C with rat anti-mouse IFN- Ab (clone
R4-6A2; BD PharMingen, San Diego, CA). Six dilutions of responder
spleen cells in complete medium were cultured without or with 10 µM
peptide epitope for 48 h. Plates were then washed and incubated
with biotinylated anti-IFN- Ab (clone XMG1.2; BD PharMingen)
followed by streptavidin conjugated to alkaline phosphatase (Boehringer
Mannheim, Indianapolis, IN). Spots were visualized using BCIP/NBT
alkaline phosphatase substrate (Promega, Madison, WI) and counted using
an automated ELISPOT plate counter (Autoimmun Diagnostika, Strassberg,
Germany). Test wells were assayed in triplicate and the frequency of
peptide-specific T cells present was calculated by subtracting the mean
number of spots obtained in the absence of peptide from the mean number
of spots obtained in the presence of peptide. All the results are
presented for the dilutions corresponding to 5 x
105 responder spleen cells per well, but <20
spots per well was considered to be a negligible response.
Flow cytometry analysis of MHC class I cell surface expression
Anti-MHC class I H-2Kk,
H-2Kb, H-2Dk,
H-2Db, FITC- or PE-conjugated Abs were purchased
from Serotec (Oxford, U.K.) and Caltag Laboratories (Burlingame, CA).
Anti-H-2Dd-PE, H-2Kd-FITC,
CD11c-PE or -FITC, mouse Ig-FITC or -PE, CD3
-Cy-Chrome,
CD45R/B220-Cy-Chrome and I-Ab-PE Abs were
purchased from BD PharMingen. Anti-rat IgG-FITC was purchased from
Sigma-Aldrich (St. Louis, MO). HB31
(anti-H-2Ld), M1/42 (pan anti-mouse MHC
class I), anti-H-2Kk clones 11.4.1 and
16.3.1N hybridomas were obtained from American Type Culture Collection
(Manassas, VA) and the Abs were used as culture supernatants, except
for 11.4.1 which was purified using protein A-Sepharose. All
anti-class I Abs were titered to find optimum staining
concentrations, and were checked for cross-reaction with the other
class I molecules present in the mice used. Total splenocytes (5
x 105) or dendritic cell (DC)
enriched-splenocytes were preincubated with rabbit serum
(Sigma-Aldrich) to inhibit FcR-mediated Ab binding, then incubated with
primary and secondary Abs on ice for 30 min each. Cells were washed two
times in PBS between and after stainings, resuspended in 0.5 ml PBS,
and analyzed on an EPICS XL flow cytometer using Expo 32 software
(Beckman Coulter, Fullerton, CA).
DC enrichment
Splenic DC were enriched using centrifugation on a metrizamide cushion as previously described (43). Briefly, after an overnight incubation of splenocytes in RPMI 1640 with 10% FCS at 37°C and 5% CO2 in cell culture-treated plastic flasks, nonadherent cells were centrifuged on a 14.5% w/v metrizamide with 10% FCS cushion at 2000 rpm in a Sorvall H1000B swing-out rotor (Newton, CT) for 10 min. Cells at the interface were harvested, washed, and resuspended in PBS with 5 mM EDTA for staining experiments.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Observations made 
20 years ago suggested that heterozygous mice
show unexpected variations in MHC class I cell surface expression
levels, depending on the combination of alleles present. However, these
studies by different groups on F1 hybrid and
recombinant strains of mice using antisera and the then available mAbs
produced conflicting results on which alleles were dominant over others
(25, 26, 44).Therefore, we reinvestigated the levels of
cell surface expression of individual class I types in commonly used
F1 hybrid mice (H-2b x
H-2k, H-2b x
H-2d and H-2d x
H-2k, see Table I
)
by contemporary flow cytometry analysis and allele-specific mAbs for
cell surface staining. This technique allowed a direct comparison of
the expression of a given class I allele in a homozygous setting with
its expression in a heterozygous setting. If the level of expression
was only dependent on gene dosage and alleles functioned independently
of each other, one should expect to find at one locus in the
F1 progeny 50% of the level of each parental
allele. Flow cytometry results obtained on splenic B and T lymphocytes
are summarized in Table II. The data
showed that the surface expression levels of alleles in
F1 mice can be significantly lower (e.g.,
H-2Dk in (BALB/c x
CBA)F1) or higher (e.g.
H-2Kb in (B6 x
BALB/c)F1) than 50% of that found in the
homozygous parental strain. The clearest difference in the level of
expression between two sets of parental alleles was found in (B6
x CBA)F1 mice, in which the levels of cell
surface expression of all four alleles were significantly different
from 50%. In these mice, H-2b alleles clearly
dominated over H-2k alleles. Similar results
were obtained with freshly isolated splenic DCs, as shown in Fig. 1. To ensure that the low relative level
of H-2Kk molecules observed in (B6 x
CBA)F1 mice was not simply a result of the
particular mAb used or restricted to female mice,
anti-H-2Kk staining was repeated on male
spleen cells using two additional different mAbs (clones 11.4.1 and
16.3.1N). For all three mAbs, the results were consistent with the data
shown in Table II, and the relative cell surface expression of
H-2Kk in male (B6 x
CBA)F1 mice was found to be lower than and
statistically different from 50% (data not shown).
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In a recent study, we identified the first
H-2Dk-restricted influenza A virus epitope,
Dk PB1349, and established
the relative immunodominance in CBA mice of the five
H-2k-restricted influenza A virus epitopes
identified to date:
KkHA259,
KkHA354,
KkNS1152,
KkNP50, and
DkPB1349 (40).
This enabled us to test the impact of the lower
H-2Dk and H-2Kk cell
surface expression in (B6 x CBA) F1 mice on
the CTL response to influenza virus, and to test whether there
is a correlation between MHC class I cell surface expression and the
magnitude of a primary CTL response. In particular, we hypothesized
that the 3-fold reduction in cell surface expression of
H-2Dk on DC may affect the
DkPB1349 response. (B6
x CBA)F1, B6, and CBA mice were infected i.n.
with influenza virus A/PR/8/34 (see Materials and Methods),
and the magnitude of CTL responses to
KkNP50,
DkPB1349,
KkHA259,
KkHA354,
KkNS1152,
DbNP366, and
DbPA224 were assayed 8 days
later by IFN- ELISPOT (Fig. 2).
(B6 x CBA)F1 mice generated a response
against all the peptides tested: the four
H-2Kk-restricted epitopes, the one
H-2Dk-restricted epitope, and the two
H-2Db-restricted epitopes. This confirms recently
published results (32) that (B6 x
CBA)F1 mice do develop a CTL response
against the DbNP366
epitope, although it has long been thought that such a response was
absent. We also confirmed that the
DbPA224 response is
significantly lower in (B6 x CBA)F1 mice
than in parental B6 mice (32). Some variations in the
magnitude of the CTL response to the different epitopes were observed
between individuals within the same group, but the average number of
IFN--producing cells specific for each epitope in (B6 x
CBA)F1 mice did not differ significantly from
that found in the corresponding control parental strain, with the
exception of the DbPA224
response, as noted above. This difference has been reported to be due
to a defect in the CTL repertoire specific for this epitope in the
F1 mice (32). Therefore, the reduced
levels of cell surface expression of the H-2Dk
and H-2Kk alleles in (B6 x
CBA)F1 mice had no detectable effect on the
generation of the H-2k-restricted CTL response to
influenza virus.
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The decrease of cell surface expression of
H-2Dk and H-2Kk molecules
found in the (B6 x CBA)F1 hybrid mice
(respectively, 35% and 46% of the levels found in CBA mice) was
clearly not sufficient to affect the vigorous CTL response that is
generated against influenza virus infection. Therefore, we looked for a
different in vivo model where competition between MHC class I alleles
may have resulted in greater down-regulation of the expression of one
or two alleles. H-2Kb-transgenic CBA mice (CBK)
(33, 34) were good candidates as these mice expressed the
three MHC class I molecules implicated in the strongest competition
that we had found: H-2Kb,
H-2Kk, and H-2Dk. It seemed
probable that H-2Kb would be overexpressed in
these transgenic mice and compete more strongly with the endogenous
H-2Kk and H-2Dk molecules.
In fact, cells from CBK mice expressed approximately twice the surface
level of H-2Kb molecules as compared with cells
from B6 mice, but this high level of expression was not accompanied by
a general increase in total MHC class I, as staining of splenic cells
with the pan class I Ab M1/42 was similar for CBK and CBA mice (data
not shown). Therefore, the levels of cell surface expression of
H-2Kk and H-2Dk molecules
on splenic T lymphocytes, B lymphocytes, and DCs were compared between
CBA and CBK mice (Fig. 3). CBK cells
showed a dramatic reduction in H-2Kk and
H-2Dk cell surface levels, only reaching 12–15%
of that of control CBA levels for H-2Kk, and
8–15% for H-2Dk. This large decrease was found
on all three cell types tested (Fig. 3).
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To investigate the functional impact of the competition between
the three MHC class I alleles in CBK mice, CBK and control CBA mice
were infected i.n. with influenza A/PR/8/34 virus, and CTL responses
were measured 8 days later in an IFN- ELISPOT assay. As expected,
control CBA mice generated a response against all the
H-2k epitopes,
DkPB1349,
KkNP50,
KkHA259,
KkHA354, and
KkNS1152 but not
KbPB1703 (Fig. 4) However, in CBK mice the
H-2k-restricted responses were severely reduced.
In fact, only responses for the
KkNP50,
DkPB1349, and
KbPB1703 epitopes were
clearly detectable, and responses against the three other
H-2Kk-restricted epitopes were essentially absent
(Fig. 4). These low responses were not due to defective infection of
the CBK mice with the virus; CBK mice generated similar numbers of
KbPB1703-specific
IFN--producing cells as control B6 mice included in the same
experiment (Fig. 5). There were two
possible explanations for the strong reduction of the responses
specific for the H-2k epitopes in CBK mice.
Either there was reduced Ag presentation because of the low MHC class I
cell surface levels, or the T cell repertoire was defective because of
altered selection in the thymus of the transgenic CBK mice. To address
this issue, CBK and control CBA mice were immunized i.p. with a
30,000-fold higher dose of influenza A/PR/8/34 virus than that used for
i.n. infection, and epitope-specific responses again measured (Fig. 6). This time, there was no significant
difference in the KkNP50
and KkHA259 responses
between CBA and CBK mice, and the
KkHA354 response was
reduced to a lesser extent (Fig. 6). Therefore, at least for these
epitopes, the specific CTL repertoire is present in the transgenic CBK
mice, and the probable explanation for the severely reduced T cell
responses after i.n. infection is reduced Ag presentation due to
competition between MHC class I molecules, which can be overcome by
massively increasing the amount of Ag.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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). Ex vivo measurement of the CTL
responses against influenza virus in these transgenic mice as compared
with control CBA mice clearly showed a correlation between the cell
surface expression level of H-2k class I alleles
and the magnitude of the antiviral CTL response (Fig. 4).
To test our hypothesis of competition between MHC class I alleles, we
conducted a systematic FACS analysis of the cell surface expression
levels of class I alleles on murine splenocytes. We postulated that if
MHC class I molecules function independently, the level of cell surface
expression of one given class I allele in a heterozygous setting
(F1 mice) should strictly follow the gene dosage
and therefore be 50% of that found in the homozygous setting (parental
strain). As we observed a consistent pattern of class I expression on
splenic B and T cells, the two sets of data were compiled together and
a statistical analysis of the results was undertaken. Although staining
for class I expression using allele-specific mAbs may to some extent be
dependent on the particular peptides bound by the class I molecule, and
therefore on the host background, our results strongly suggest that MHC
class I cell surface expression does not simply follow gene dosage. The
expression of at least one allele in each F1
hybrid was found to be significantly higher or lower than the predicted
value of 50% (Table II), and for the H-2Kk
molecule in (B6 x CBA)F1 mice this was
confirmed using three different allele-specific mAbs. The competition
seemed more apparent between certain combinations of class I molecules,
i.e., it is an allele-specific effect. For example, in (B6 x
BALB/c)F1 mice, only H-2Kb
was found to have a cell surface level significantly different to 50%
of that of the corresponding parental strain, whereas all four
H-2Kb, H-2Db,
H-2Kk, and H-2Dk class I
molecules in (B6 x CBA)F1 mice were above
or below 50%, strongly suggesting that the H-2b
alleles interfere with H-2k alleles to a greater
extent than with H-2d alleles. Our results are
different from previous findings reported by O’Neill (26)
describing domination of H-2Dk and
H-2Kk over H-2Db and
H-2Kb in (B10xB10.BR)F1
mice. The reported results of domination of H-2k
over H-2b alleles seemed consistent with in vivo
experiments showing that the presence of the
H-2Kk molecule altered the development of
antiviral CTL responses restricted by other MHC class I molecules in
the host (29, 30, 31). In particular,
H-2Db-restricted CTL responses against influenza
virus were abrogated in mice expressing H-2Kk,
although the nucleoprotein epitope
DbNP366 was extremely
immunodominant in H-2b mice. However, we have
found that mice expressing the H-2Kk molecule do
indeed develop a CTL response specific for
DbNP366 after influenza
virus infection (Fig. 2), suggesting that the absence of a response
seen in previous studies was due to the necessity of secondary
restimulation with Ag for the detection of lysis. This confirms the
results reported recently by Doherty and coworkers (32)
who, in addition, showed that the low response in (B6 x
CBA)F1 mice against
DbPA224 (Fig. 2) was due to
a specific depletion of V7+
CD8+ T cells, possibly induced by the
H-2Dk molecule. The relatively low cell surface
expression of H-2Dk described in the current
study (35% that of in parental CBA) is not inconsistent with this
hypothesis, as it has been shown that the level of MHC class I is 2- to
3-fold higher on thymic DC than splenic DC (9). According
to the "avidity/density" model of thymic selection
(45), this higher level of total class I molecules could
still allow the number of H-2Dk and
H-2Kk molecules to reach a sufficient cell
surface level to ensure the normal T cell education process, especially
negative selection.
The generation of stably transfected cell lines has confirmed the
phenomenon of competition for cell surface expression between different
MHC class I molecules in vitro. Again, the effects are allele-specific
and, interestingly, the strongest competition occurs in interspecies
transfections when a class I H chain from one species is introduced
into a cell line from a different species (K. G. Gould,
unpublished observation). There are specific examples of human class I
alleles causing strong down-regulation of cell surface endogenous rat
and mouse class I molecules, and mouse class I alleles causing strong
down-regulation of endogenous hamster class I surface expression.
Current work is aimed at identifying the precise mechanism of this
competition, with competition for association with
2-microglobulin the most obvious candidate
mechanism (46). Intranasal infection of transgenic CBK and
control CBA mice showed that an 7-fold down-regulation of cell
surface expression of H-2k class I alleles
strongly reduced the H-2k-resticted CTL response
against influenza virus (Figs. 3 and 4). This was probably due to the
corresponding reduction in Ag presentation ability rather than defects
in the CTL repertoire of the transgenic mice, because immunization of
CBK mice with a much higher dose of virus was able to restore, at least
partially, normal CTL responses against the virus (Fig. 6). This
restoration at high Ag dose was most likely due to an increased
proportion of the H-2k class I molecules on DC
presenting influenza-derived peptide epitopes, reaching the levels
required to generate efficient CTL responses. It has been demonstrated
that the magnitude of the responding CTL population in vivo following
viral infections is essentially proportional to epitope density
(47). However, the 2- to 3-fold reduction in cell surface
class I expression observed in F1 hybrid mice was
not sufficient to affect the CTL response against influenza virus (Fig. 2). This suggests that class I levels (and specific class I-peptide
complexes) must be reduced below a certain threshold level before CTL
responses are affected, at least for strong antiviral responses. The
situation may be rather different for weaker CTL responses, such as
anti-tumor responses, where even slight reductions in MHC class I
levels could have significant consequences. It is also possible that
some competition between different class I molecules occurs without any
gross changes in steady-state cell surface expression levels. For
example, the introduction of a new type of class I molecule could
affect the trafficking rate of other class I molecules, which could be
important in deciding the immunodominance hierarchy of any CTL
response. Preliminary results suggest that the strong down-regulation
of the H-2k alleles in the transgenic CBK mice
is also found on thymic epithelial cells (data not shown), so although
immunization with high doses of Ag does partially restore the CTL
response, we cannot exclude the possibility that CBK mice also produce
less H-2k-restricted CTL precursors than CBA
mice.
Does competition between MHC class I molecules have any relevance for human immune responses? To our knowledge, no study has been undertaken of competition between HLA class I molecules in humans, although it is known that different HLA class I H chains have varying affinities for components of the Ag presentation pathway, and are expressed at the cell surface at different levels. In fact, there is remarkably little data concerning the normal variation between individuals in the cell surface levels of specific HLA class I molecules, and the introduction of DNA-based HLA typing methods means this information is even less likely to become available. One report has suggested that specific HLA class I levels do vary significantly between individuals and are genetically determined (48). However, it is not even clear whether homozygous individuals tend to express higher cell surface levels of specific HLA class I molecules than heterozygous individuals. Testing the hypothesis of competition between HLA class I molecules is a difficult task because of the multiplicity of HLA class I alleles (over 600 described to date, see http:/www.ebi.ac.uk/imgt/hla). Recently, Boon et al. (49) reported a systematic study of the influence of the background HLA-A and -B genotypes of individuals on the magnitude of their CTL response against influenza A virus. They found that the CTL response restricted by a particular class I allele could be affected by the other alleles present. For example, the frequency of CTL specific for the HLA-B8-restricted epitope NP380–388 was 3-fold lower in HLA-B27-positive individuals than in HLA-B27-negative individuals (49). This is consistent with possible competition between class I alleles, however no data on cell surface levels of the different class I alleles present in the donors was presented. Alternatively, for any particular infection, the introduction of a new type of class I molecule could lead to a new hierarchy of immunodominance in the CTL response simply because of the relatively greater affinity of the new epitopes presented by that molecule, i.e., competition between epitopes rather than between class I molecules themselves. Competition between MHC class I molecules might have the greatest biological significance when functional down-regulation affects an allele associated with susceptibility or resistance to a particular disease. For example, down-regulation of HLA-B27 might have a positive effect in reducing the risk of developing ankylosing spondylitis (50), and conversely, down-regulation of HLA-A2 in human T lymphotropic virus type 1 infected individuals might result in an increased risk of developing the human T lymphotropic virus type 1-associated myelopathy/tropical spastic paraparesis (51). Therefore, investigation of the cell surface expression levels of a few combinations of the most common HLA class I alleles, and in particular those associated with specific diseases, could give an insight as to whether competition between HLA class I molecules does occur and has any biological significance.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Keith G. Gould, Department of Immunology, Faculty of Medicine, Imperial College of Science, Technology and Medicine, Norfolk Place, London W2 1PG, U.K. E-mail address: k.gould{at}ic.ac.uk
3 Abbreviations used in this paper: i.n., intranasally; DC, dendritic cell.
Received for publication March 28, 2002. Accepted for publication September 12, 2002.
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References |
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2-microglobulin and presentation of a viral peptide. J. Immunol. 155:3481.[Abstract]
2-microglobulin: differential effects of inhibition of glycosylation on class I subunit association. Eur. J. Immunol. 18:801.[Medline]
-producing T cells. J. Immunol. Methods 227:99.[Medline]
2m in vivo. Immunogenetics 43:384.[Medline]
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