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Department of Immunology, St. Jude Children’s Research Hospital, Memphis, TN 38105
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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-based flow cytometric assay. The depressive
effect of H2Kk was very apparent for the influenza
DbPA224 epitope and was also reproduced when
CTL activity was measured for H2Db-expressing targets
pulsed with the immunodominant NP366 peptide. The secondary
CD8+IFN-+
DbNP366-specific response was much greater in
parental H2b than in H2kxbF1
mice, but the sizes of the CD8+ sets specific for
KkNP50 and DbNP366 were
essentially equivalent in the F1 animals. Thus, although
the immunodominance profile associated with
DbNP366 is lost when H2Kk is also
present, the response is still substantial. A further, MHC-related
effect was also identified for the KkNS1152
epitope, which was consistently associated with a greater
CD8+IFN-+ response in
H2KkDb recombinant than in
(H2KkDk x
H2KbDb)F1 mice. The diminished
DbPA224 response in
H2kxbF1 mice was characterized by loss of a
prominent Vß7 TCR responder phenotype, supporting the idea that
TCR deletion during ontogeny shapes the available repertoire. The
overall conclusion is that these MHC-related immunodominance
hierarchies are more subtle than the early CTL assays suggested and,
although inherently unpredictable, are unlikely to cause a problem for
peptide-based vaccine strategies. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Several different types of experiments were performed in efforts to take this observation further. Naive B10.A(4R) T cells (H2KkDb) were depleted of alloreactive potential by in vivo filtration through lethally irradiated KbDb mice, then stimulated with vaccinia virus in an additional set of irradiated KbDb recipients (3). Under these conditions the vaccinia-specific KkDb T cells showed potent, virus-specific, H2Db-restricted CTL activity. Later limiting dilution analysis (LDA)4 to determine influenza-specific CD8+ T cell frequencies showed that significant H2Db-restricted memory populations were generated in mice that also expressed H2Kk (4). Both approaches thus indicated that the concurrent presence of H2Kk throughout ontogeny did not greatly compromise the development of H2Db-restricted CTL precursors (CTLp) specific for vaccinia virus, although there was an effect on the generation of CTL effectors in normal mice.
The opposite conclusion was drawn from other experiments that analyzed response patterns for H2KbDb T cells from mice that had been neonatally tolerized to H2Kk (5). In this case the vaccinia-specific, H2Db-restricted CTL response was profoundly diminished. The favored interpretation was that the presence of H2Kk during development resulted in the deletion of CD8+ T cells that could recognize vaccinia virus associated with H2Db.
These studies were all performed a very long time ago, before we
understood that the primary function of MHC glycoproteins is to present
viral peptides to the TCR (6, 7). The assays used (CTL and
LDA) were either minimally quantitative (CTL) or at an early stage of
development and far from optimized (LDA). We did not know that distinct
CD8+ T cell clones could be specific for
different peptides from the same virus bound to the same MHC class I
glycoprotein (7, 8). Even so, it is clearly important as
we move to the use of peptide-based vaccines (9) that we
understand whether such MHC-related immunodominance hierarchies are
real and, if so, how they operate. The experiment reported here used
short term peptide stimulation followed by staining for cytoplasmic
IFN- (8, 10, 11) to look at the relationship between
H2Kk and H2Db (1, 2) for the influenza-specific CD8+ T cell
response. This approach gives very similar numbers (8, 10, 11) to those detected by staining with tetrameric complexes of
MHC class I glycoprotein plus peptide (tetramers). Tetramer reagents
were not available for most of the epitopes analyzed in this study.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Female C57BL/6J (B6, H2b), C3H/HeJ (C3H, H2k), B6xC3HF1 (B6C3F1, H2kxb), B10.BR (H2k), and B10.A(2R) (H2KkDb) mice were purchased from The Jackson Laboratory (Bar Harbor, ME). They were anesthetized at 8 wk of age by i.p. injection with avertin (2,2,2-tribromoethanol) and were challenged intranasally (i.n.) with 106.8 EID50 of the HKx31 (H3N2) influenza A virus (12). Memory mice for secondary challenge experiments were injected i.p. at least 6 wk previously with 108.5 EID50 of the PR8 influenza virus (11). At the time of sampling, the mice were anesthetized and exsanguinated from the axillary artery. Lymphocytes were obtained from the pneumonic lung by bronchoalveolar lavage (BAL), and adherent cells were removed by incubating them on plastic for 1 h at 37°C (12). Peritoneal exudate lymphocytes (PEL) were processed in the same way. Spleen and mediastinal lymph node (MLN) samples were disrupted and enriched for CD8+ T cells by incubation with mAbs (PharMingen, San Diego, CA) to CD4 (GK1.5) and MHC class II glycoprotein (M5/114.15.2), followed by anti-rat and anti-mouse Ig-coated magnetic beads (Dynal, Oslo, Norway).
Peptides, epitopes, and the Pep assay
The influenza virus nucleoproteins ASNENMETM (NP366–374) and SDYGERLI (NP50–57), nonstructural protein EEGAIVGEI (NS1152–160), nuclear export protein RTFSQLI (NS2114–121), polymerase 2 SSLENFRAYV (PA224–233), and matrix protein MGLIYNRM (M128–135) used in this study have all been described previously (6, 8, 13, 14). They were synthesized at the Hartwell Center, St. Jude Children’s Research Hospital using a model 433A peptide synthesizer (Applied Biosystems, Berkeley, CA) and were purified by HPLC. The H2K or H2D epitopes associated with these peptides are identified as DbNP366, DbPA224, KbNS2114, KkNP50, KkNS1152, and KbM1128.
The Pep assay (8, 10, 11) used spleen MLN and BAL
populations that were enriched for CD8+ T cells
and cultured for 5 h in 96-well round-bottom plates (Costar,
Corning, NY) at a concentration of 5–8 x
105 cells/well in 200 µl of RPMI 1640 medium
containing 10% FCS, 10 U/ml human rIL-2, and 5 µg/ml Brefeldin A
(Epicentre Technologies, Madison, WI) in the presence or the absence of
1 µM viral peptide. The T cells were then washed and stained with
anti-mouse CD8
-FITC Ab (PharMingen, San Diego, CA).
Nonspecific Fc binding was blocked using anti-mouse CD16/32
(PharMingen). The cells were fixed in 1% formaldehyde in PBS for 20
min, then permeabilized in PBS/0.5% saponin for 10 min before staining
with a conjugated mAb to mouse IFN- (PE-XMG 1.2). The specificity of
the staining reaction was checked initially by blocking with excess
purified cytokine. Isotype control Ab was also used. The data were
acquired on a Becton Dickinson FACScan or FACScalibur flow cytometer,
then analyzed using CellQuest software (Becton Dickinson
Immunocytometry Systems, San Jose, CA). In each assay, the percentage
of CD8+IFN-+ without
peptide (<0.2%) was subtracted from the percentage of
CD8+IFN-+ with peptide
to give the percentage of specific CD8+ T
cells.
ELISPOT assay
The numbers of memory T cells in the spleens of mice primed with
the PR8 virus were determined by the IFN- ELISPOT assay (15, 16). Nitrocellulose-bottom 96-well plates (Millipore, Bedford,
MA) were coated overnight at 4°C with rat anti-mouse IFN- Ab
(clone R4-6A2 from PharMingen). Dilutions of responder cells in
complete medium were cultured for 48 h with 5 x
105 syngeneic feeders pulsed with (1 µM) or
without peptide and 10 U/ml recombinant human IL-2. The plates were
then washed and incubated with a biotinylated mAb to IFN- (clone XMG
1.2) followed by streptavidin-alkaline phosphatase and developed using
5-bromo-4-chloro-3-indolyl-phosphate/nitro blue tetrazolium alkaline
phosphatase substrate (Sigma, St. Louis, MO). Responses were considered
positive when there were >10 ELISPOTs/well and the number of
peptide-pulsed feeder ELISPOTs was more than two times the
number of unpulsed feeder ELISPOTs. The frequency of peptide-specific
CD8+ T cells present in the responding population
was calculated by subtracting the mean number of spots for feeders with
no peptide from the mean number of spots with peptide-pulsed
feeders.
CTL assay
The target H2k- or H2Db-transfected L-929 cells (L cells) were labeled with Na51Cr for 1 h, pulsed with viral peptides or infected with the HKx31 influenza A virus for 60 min, washed, then plated at 5000 targets/well (8). The target cells were washed twice and incubated with the effector populations for 5 h before harvesting supernatants for gamma counting. Two-fold lymphocyte dilutions were assayed in triplicate, while untreated and Triton-disrupted controls were measured in quadruplicate. The percent specific lysis was calculated as 100 x (51Cr release from targets with effectors - 51Cr release from targets alone)/(51Cr release from targets with Triton). The level of 51Cr release from targets incubated in the absence of T cells did not exceed 15% of the total Triton-mediated 51Cr release. This background value was subtracted to give the values presented here.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The initial finding (1) that the influenza-specific,
H2Db-restricted response was substantially
greater in the absence of H2Kk was made using
virus-infected L cell
(KkDk) and MC57G
(KbDb) targets and CTL
populations taken directly from PR8-primed mice challenged i.n. with
the HKx31 virus. This secondary challenge (HKx31
PR8) experiment
(1, 11) was repeated, except that the CTL targets were L
cells expressing DbNP366
(Fig. 1
, A–D) and
KkNP50 (Fig. 1, E–H). The level of
DbNP366-specific lysis was
greater in every case for the parental B6
(KbDb) than for
B6C3F1
(KkDk x
KbDb) effectors from the
spleen, BAL and MLN (Fig. 1, A–D). An identical result was
recorded for the BAL population recovered from mice after primary
infection with the HKx31 virus (Fig. 2). The quality of CTL recognition did
not, however, differ for the B6 and B6C3F1
responses to the NP366 peptide, as the cut-off
point for lysis of the peptide-pulsed L929-Db
targets was 10-10 M in each case (Fig. 2).
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) could, however, cause us to question
the exclusivity of this F1 effect to the
H2Db-restricted response (1).
Cytotoxicity associated with the recognition of
KkNP50 by the secondarily
stimulated B6C3F1 CTL was also diminished
compared with the level of specific 51Cr release
caused by the C3H (KkDk) T
cells, with the effect being most obvious for the BAL population (Fig. 1G). We did not persist further with this, as we clearly now
have much better assays (8, 11, 14, 16) for measuring
virus-specific CD8+ T cell responses (see
subsequent sections). Also, our capacity to analyze the
H2k-restricted response is limited by the fact
that only two epitopes (13) have been identified
(KkNP50 and
KkNS1152), and it seems
likely from the more detailed analysis that has been performed with the
H2b haplotype (6, 8, 14) that there
are more to be found. T cell memory
Other early LDA studies indicated that the numbers of
H2Db-restricted memory CTLp were not necessarily
significantly different for mice expressing H2Db
in the presence or the absence of H2Kk
(4). This was confirmed using the IFN- ELISPOT assay
(Fig. 3), which tends to give lower
values than the Pep protocol (11), but, because the
lymphocytes are diluted, allows virus-specific memory T cells to be
detected at lower frequencies. The prevalence of memory T cells
specific for DbNP366 was
comparable for the B6 and B6C3F1 mice. This was
also true for the set reactive to
KkNP50 in the C3H and
B6C3F1 mice (Fig. 3). The diminished recall of
CTL activity for the KkNP50
and DbNP366 epitopes in the
F1 group (Fig. 1) is thus not obviously explained
by the relative availability of memory T cells (Fig. 3).
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+ T cells in parental and
F1 mice
The primary and secondary responses (HKx31PR8) following i.n.
exposure to the HKx31 virus were then analyzed using the Pep assay
for parental (B6 and C3H) and F1 mice. The
results for the DbNP366-
and KkNP50-specific sets
are given as the percentage of cells staining in the BAL, MLN, and
spleen for the H2k, H2b,
and H2kxbF1 mice in Fig. 4, while the total cell counts for
populations reactive to
DbNP366,
KkNP50,
KkNS1152, and
KbNS2114 are shown for the
F1 group only in Fig. 5. Cumulating the prevalence data for the
different epitopes in the various sites sampled indicates that the
magnitudes of the primary F1 and parental
responses are essentially equivalent up to 10 days after infection
(Fig. 4, A, B, E, F,
I, and J). The numbers of
CD8+
DbNP366 T cells in the
F1 BAL and spleen on day 13 were, however, 2- to
3-fold lower than the parental values (Fig. 4, A,
E, and I). The HKx31 virus is generally cleared
from the lung within 10 days of primary challenge, so the
CD8+
DbNP366+
response seems to resolve more rapidly in the F1
than the B6 mice (17).
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, C,
G, and K), an effect that was much less apparent
for KkNP50 encountered in
the H2k and H2kxb
F1 situations (Fig. 4, D,
H, and L). However, when we translated the
percentages into cell numbers, the magnitudes of the
DbNP366- and
KkNP50-reactive populations
were essentially comparable for the B6C3F1
response (Fig. 5). The divergence in relative prevalence of the
DbNP366- and
KkNP50-reactive sets is
thus seen between the parent and the F1, not
within the F1 group. It is important in this
regard to note that the scales in Fig. 4 are very different for the
DbNP366-specific (Fig. 4, C, G, and K) and
KkNP50-specific (Fig. 4, D, H, and L) populations, with the B6
results reflecting the dominance of
DbNP366 that we have
recognized previously for the secondary influenza-specific response in
B6 mice (8, 11, 17). Responses to the DbPA224 and KkNS1152 epitopes
We recently described (8) a new epitope
(DbPA224) that is at least
as prominent as DbNP366 in
the primary, but not the secondary, response of B6 mice following i.n.
challenge with the HKx31 virus. The same relationship was found for
virus-specific CD8+ T cells in the spleen and PEL
population from naive H2b mice challenged i.p.
with the PR8 virus (Fig. 6, A
and C), the protocol used to prime for the secondary
response (Figs. 1, 2, 4, and 5). However, this equivalence between the
DbNP366- and
DbPA224-reactive sets (Fig. 6, A and B) was not apparent for
H2kxb F1 mice, in which
the numbers of T cells specific for
DbNP366 were much higher
(Fig. 6, B and D). The lower prevalence of
DbPA224-specific T cells in
F1 mice was also confirmed following primary i.n.
challenge with the HKx31 virus (Fig. 7, A, C, and E). The profile for the
DbPA224-reactive set in the
B10.A(2R) H2KkDb
recombinant (Fig. 7, B, D, and F) was
intermediate between that for the
H2KbDb parent (Fig. 6, B and D) (8) and the
(H2KkDk x
H2KbDb)
F1 (Fig. 6, A and C, and
Fig. 7, A, C, and E).
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, B, D, and F). However,
KkNS1152 was clearly less
prominent following both primary (Fig. 5, A–C, and Fig. 7, A, C, and E) and secondary (Fig. 5, D–F) challenge of the B6C3F1 mice.
Comparison of primary BAL populations from congenic B10.BR
(KkDk) and B10.A (2R) mice
also showed a relatively greater response to
KkNS1152 in the recombinant
(Table I) than in the parental strain, an
impression that was confirmed by further analysis using C3H
(H2KkDk) mice (Fig. 8). The response to
KkNS1152 thus seems to be
lower when H2Dk is also present.
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The
CD8+DbNP366+
response is characterized by prominent usage of a spectrum of
Vß8.3+ TCRs associated with a variety of TCR
-chains (18). Recent analysis indicates that Vß7
dominates the
CD8+DbPA224-specific
set generated in B6 mice (G.T.B. and P.C.D., unpublished observations).
We thus asked whether the low
CD8+DbPA224
response in the H2kxbF1
mice might reflect some change in the pattern of TCR involvement. This
was indeed found to be the case. When HKx31-immune
H2b and H2kxb
F1 spleen populations were stimulated separately
in vitro with the PA224 (Fig. 9A) or
NP366 (Fig. 9B) peptides, the
diminished response in the F1 animals was
associated with a complete absence of Vß7 in cultures established
from all but one of five mice (Fig. 9A). There was, however,
no difference in the Vß8 staining profile for the B6 and
B6C3F1 mice (Fig. 9B). The effect for
DbPA224 could reflect
clonal deletion of cross-reactive Vß7+ T cells
specific for self peptide(s) presented in the context of
H2Kk or H2Dk
(5). The higher
DbPA224-specific response
(spleen and MLN; Fig. 7) in the
H2KkDb (compared with the
H2KkDk x
KbDb
F1) mice might indicate that the defect for
DbPA224 is more likely to
be associated with H2Dk than with the
H2Kk allele implicated in the early analysis of
immunodominance hierarchies (1, 2). However, it is also
possible that the Ag involved in the putative deletion of the
Vß7+
DbPA224+-specific
set is a peptide from the C3H background presented by
H2Kk. This will be analyzed further.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We found that the magnitude of the primary
DbPA224-specific response
is much lower in H2kxbF1
than in H2b mice when measured quantitatively by
the Pep assay. However, the minimal CTL activity associated with
DbPA224 (8)
indicates that this epitope is poorly presented on virus-infected cell
lines, so the diminished numbers of
DbPA224-specific T cells in
H2kxbF1 mice fails to
explain the H2Db-restricted difference between
F1 and parent detected earlier by cytotoxicity
(1). On the other hand,
DbNP366 is a potent CTL
target. The primary response to
DbNP366 measured as numbers
of CD8+IFN-+ cells was
at an equivalent level (at least to day 10) in the
H2kxbF1 and
H2b mice, although the level of specific
51Cr release caused by freshly isolated BAL
populations was lower in the F1 group. It thus
seems that CD8+ T cell frequency does not
necessarily predict the magnitude of differentiated CTL function, at
least in the primary response to the influenza A viruses.
Unfortunately, we do not currently have an assay available that allows
CTL activity to be measured at the single-cell level.
While the numbers of
DbNP366-specific
CD8+ memory T cells were comparable for
PR8-primed H2kxbF1 and
H2b mice immediately before i.n. challenge with
the HKx31 virus, the extent of further clonal expansion
(17) showed the hierarchy for the
CD8+IFN-+ set that would
have been predicted from the CTL assays. The dominance by the
DbNP366-specific population
during the secondary influenza-specific CD8+ T
cell response in H2b mice had led to the
impression that DbNP366 is
some sort of "superepitope" (8, 11). However, this is
not the case in the
H2kxbF1, where the
responses to DbNP366 and
KkNP50 are essentially
equivalent. The relative prevalence of a particular epitope-specific
CD8+ population is clearly a function of the
spectrum of MHC glycoproteins that are expressed in the responder
environment. This effect is also seen for
KkNS1152, which, compared
with KkNP50, shows the
hierarchy
H2KkDb>H2KkDk>(H2KkDk
x
H2KbDb)F1.
The primary and recall responses to different epitopes were similar in magnitude for the H2kxbF1, but not the H2b, mice. The major difference is the prominence of the DbNP366-specific set in the parental strain following secondary challenge. The situation for the H2kxbF1 is much more comparable to that described previously for epitopes derived from Listeria monocytogenes (19). Immunodominance hierarchies apparently become unpredictable with the addition or removal of other MHC glycoproteins.
The idea that H2Db-restricted CD8+ T cells are deleted during thymic development as a consequence of exposure to self peptides presented by H2k glycoproteins throughout ontogeny could explain the much lower response to DbPA224 in H2kxbF1 than in H2b mice (5). This cross-tolerance concept was developed before it was known that MHC-restricted CD8+ T cells are specific for viral peptides. The observation that such effects are apparent for one (DbPA224), but not another (DbNP366), epitope makes sense in the context of established models of self tolerance (20, 21, 22). It is certainly the case that the absence of key TCRs in the mature repertoire can diminish the magnitude of a CD8+ T cell response (reviewed in Ref. 7).
The obvious question is whether we should be concerned about MHC-related immunodominance hierarchies as we move to develop vaccines that incorporate peptides expressed by a spectrum of MHC molecules. A case in point is the polytope approach that uses linked viral peptides that bind a range of HLA glycoproteins to protect, for instance, against EBV infection (9, 23). The results presented here indicate that any MHC-related hierarchies are generally much less absolute than suggested by the early CTL assays and are not likely to cause a problem for a vaccine incorporating multiple peptides. Even so, it is appropriate to assure that the peptides used are recognized widely by people that express the particular HLA glycoprotein.
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Footnotes |
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2 Current address: Addenbrookes Hospital, Hills Road, Cambridge, United Kingdom CB2 2QQ.
3 Address correspondence and reprint requests to Dr. Peter C. Doherty, Department of Immunology, St. Jude Children’s Research Hospital, 332 North Lauderdale, Memphis, TN 38105.
4 Abbreviations used in this paper: LDA, limiting dilution analysis; i.n., intranasally; BAL, bronchoalveolar lavage; ELISPOT, enzyme-linked immunospot; MLN, mediastinal lymph node; H, influenza hemagglutinin; M, matrix protein; N, neuraminidase; PA, polymerase 2 protein; PEL, peritoneal exudate lymphocytes; NP, nucleoprotein; NS1, nonstructural protein; NS2, nuclear export protein.
Received for publication March 24, 2000. Accepted for publication June 14, 2000.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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A. C. M. Boon, G. de Mutsert, R. A. M. Fouchier, K. Sintnicolaas, A. D. M. E. Osterhaus, and G. F |
), while the BAL and MLN samples were pooled
from the B6 (
), C3H (
), or B6C3F1 (
) mice.
) syngeneic spleen cells.
Peptide-specific IFN-
) mice using the Pep
) and
KbNS2114 (
