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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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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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subsequent to in vitro stimulation
with peptide (Pep assay). Following primary intranasal (i.n.)
challenge with the HKx31 virus, the numbers of
CD8+DbPA224+
and
CD8+DbNP366+
T cells recovered from the regional mediastinal lymph nodes (MLN), the
spleen, and the pneumonic lung are essentially equivalent, although the
peak response to DbPA224
precedes that to DbNP366
(6).
There are, however, major differences between the
DbNP366- and
DbPA224-specific responses
that may explain why the NP peptide was first described in 1986
(3), while the PA epitope was not identified for another
14 years (6). First, although the
CD8+DbPA224+
and
CD8+DbNP366+
populations both show potent CTL activity when assayed on
peptide-pulsed, syngeneic target cells, only the
CD8+DbNP366+
effectors are strongly lytic for comparable cells infected with the
HKx31 virus (6). Second, although the numbers of
CD8+DbPA224+
and
CD8+DbNP366+
memory T cells are equivalent in mice primed at least 1 mo previously
with the influenza A/Puerto Rico/8/34 (PR8, H1N1) virus, the recall
response to DbNP366
following i.n. challenge with the HKx31 virus is 5- to 10-fold greater
than that to DbPA224.
Finally, the early characterization of the NP peptide was based on CTL
assays with cell lines (3), while the
DbPA224 epitope was
identified by ex vivo screening of lymphocytes from mice with a
primary, acute HKx31 infection using the Pep assay (6)
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The fact that clonal expansion of the
CD8+DbPA224+
and
CD8+DbNP366+
populations is equivalent following primary, but not secondary,
challenge (6) seems to refute our earlier hypothesis that
both the magnitude of CD8+ T cell memory and the
consequent recall response are a direct reflection of the clonal burst
size following the initial encounter with Ag (9). The
comparison between the
CD8+DbPA224
and
CD8+DbNP366
responses suggests that quality may be at least as important as
quantity when considering the nature of immune memory (8, 10). Subsequent analysis has established that
CD8+DbPA224-
and
CD8+DbNP366-specific
T cells indeed differ in their capacity to synthesize IFN- and
TNF-
following stimulation with peptide, with the
CD8+DbPA224+
set showing the highest response for both cytokines. The implications
of this finding are currently being explored in other experiments.
Earlier studies suggested that an established memory CD8+ T cell response will suppress the clonal expansion of naive CD8+ populations specific for the same, or a different, epitope (11, 12). The simplest explanation for this would be that the memory CD8+ T cells become effectors more quickly and eliminate the Ag-presenting dendritic cells before the primary response gets underway (13). This constraint is obviously important when thinking about peptide vaccination protocols for viral or tumor immunity. The present experiments analyze the cycling characteristics of adoptively transferred CD8+DbNP366+ T cells and measure the effect of this population on primary response to the DbPA224 and DbNP366 epitopes.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Conventional Thy-1.2+ and congenic Thy-1.1+ B6 female mice were purchased from The Jackson Laboratory (Bar Harbor, ME). The Thy-1.1+ donors were primed i.p. with PR8 (107.9 50% egg infective dose (EID50)) and boosted twice at 4- to 6-wk intervals, first by i.n. infection with HKx31 (106.8 EID50), then i.p. with 3 x 107 PFU of a recombinant vaccinia virus (VV-NP) encoding a truncated influenza NP gene gene (14). These immune Thy-1.1+ mice were sampled after a further 4–6 wk to provide CD8+DbNP366+ T cells for the transfer experiments. Some of the B6 Thy-1.2+ recipients were later challenged i.n. with 106.8 EID50 of the HKx31 virus or with 105.6 EID50 of the non-cross-reactive B/Hong Kong/73 (B/HK) influenza B virus (15). The NP366–374 peptide is common to PR8, HKx31, and VV-NP, but not to B/HK.
Peptides and tetramers
The NP366–374 (ASNENMETM) and polymerase A (PA224–233, SSLENFRAYV) peptides were made at the Center for Biotechnology, St. Jude Children’s Research Hospital, using a PerkinElmer (Norwalk, CT) 433A peptide synthesizer, and then purified by HPLC. The production and characterization of the DbNP366 and DbPA224 tetramers have been described previously (1, 6).
Sorting and transfer of CFSE-labeled Thy-1.1+CD8+ DbNP366+ T cells
Single-cell suspensions were prepared from the spleens of the triple-primed Thy-1.1+ mice, erythrocytes were lysed, and B cells were removed by panning in T175-cm2 flasks coated with goat anti-mouse IgG/IgM (Jackson ImmunoResearch, San Francisco, CA) for 1 h at 37°C in 5% CO2. The nonadherent cells were incubated with mAbs to CD4 (GK1.5) and MHC class II (TIB120), followed by sheep anti-mouse Ig- and sheep anti-rat Ig-coated beads (Dynal, Oslo, Norway), then enriched for the CD8+ subset by magnetic depletion. The predominantly CD8+ population was resuspended at 20 x 106 cells/ml in PBS/0.1% BSA (sort buffer), stained with the PE-conjugated DbNP366 tetramer (1:100 in sort buffer) for 1 h at room temperature, washed, and stained with anti-CD8 FITC (BD PharMingen, San Diego, CA) for 30 min at 4°C. After a further wash, the CD8+DbNP366+ set was separated using a MoFlo (Cytomation, Fort Collins, CO) high-speed cell sorter, resuspended at 30–50 x 106 cells/ml, and stained with CFSE (16). The cells were then washed twice in PBS, resuspended at 107 cells/ml in PBS, and injected (200 µl) i.v. into normal B6 Thy-1.2+ recipients.
Flow cytometric analysis and sampling the recipients
Aliquots of the donor DbNP366+ populations were analyzed by flow cytometry both before and after cell transfer, while the response profiles of the immunologically intact recipients were measured by analyzing Thy-1.2+ CD8+ T cells. The recipient mice were anesthetized with Avertin (2,2,2-tribromoethanol), the axillary artery was cut, and PBL were recovered from heparinized blood. The CD8+ set was enriched magnetically (see above) from single-cell suspensions of the MLN and spleen. Inflammatory cell populations recovered from the infected lung by bronchoalveolar lavage (BAL) were adsorbed on plastic for 1 h at 37°C to remove most of the macrophages. The lymphocytes were then stained with the PE-DbNP366 and PE-DbPA224 tetramers (1:100 in PBS/0.1% BSA/0.02% sodium azide, FACS buffer) for 1 h at room temperature, washed, stained with a mixture of anti-CD8-Tricolor (Caltag Laboratories, San Francisco, CA) and biotinylated anti-Thy-1.1 or anti-Thy-1.2 (1 in 500; BD PharMingen), followed by streptavidin-conjugated allophycoerythrin (1 in 500; Molecular Probes, Eugene, OR). Some of the donor DbNP366+ T cells were also stained with FITC-conjugated mAbs (BD PharMingen) to CD44, CD62L, and CD69. A minimum of 100,000 lymphocyte/CD8+-gated events/sample was collected on a FACSCalibur (BD Biosciences, San Jose, CA) and analyzed using CellQuest software.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Flow cytometric analysis established that 40–50% of
CD8+ T cells enriched from the spleens of
triple-primed (PR8/HKx31/VV-NP) Thy-1.1+ mice at
4–6 wk after the final boost with VV-NP bound the
DbNP366 tetramer (data not
shown). The
Thy-1.1+CD8+DbNP366+
(donor
DbNP366+)
T cells were isolated by cell sorting, then aliquots were stained to
demonstrate the
CD44highCD62LlowCD69low
phenotype (Fig. 1
, A–D) of
recently primed, splenic CD8+ memory T cells
(1, 17, 18). The remaining cells were then labeled with
the fluorescent dye CFSE (16) and transferred into naive
B6 Thy-1.2 recipients. These Thy-1.1+ cells were
detected 2 days later in the spleen and PBL compartments of the
recipients (Fig. 1, I–K) at levels comparable to those
found previously in mice primed i.p. with the H1N1 virus
(1). At this stage, the donor
DbNP366+
cells were all CFSEhigh (Fig. 1E), and
the CFSEhigh set retained the
CD44highCD62LlowCD69low
phenotype (Fig. 1, F–H). No donor
DbNP366+ T
cells were found in the regional MLN (Fig. 1L).
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A). The numbers were
constant for 10 days, fell significantly (p <
0.04) over the next week, then remained at much the same level through
the remainder of the sampling period. The progressive diminution in the
intensity of CFSE staining (50% loss at each cell division) indicates
that the tetramer+ T cells were cycling for at
least the first 3 wk after cell transfer (Fig. 2B). The
declining counts could reflect either that some of the proliferating
cells die, or move out of the spleen to other tissue sites
(19).
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The next question was whether the donor
DbNP366+ T
cells could generate a recall response following i.n. challenge with
the HKx31 influenza A virus. A comparable group of mice was infected at
the same time (day 2 after cell transfer) with the B/HK influenza B
virus, both to determine how another respiratory infection would
influence T cell localization patterns and to look for evidence of
bystander activation (20, 21, 22). Uninfected controls that
were sampled 15 days after cell transfer had significant numbers of
donor
DbNP366+ T
cells in the spleen (see legend to Fig. 3), fewer in the BAL, and none in the MLN
(Fig. 3, A–C). The population in the spleen (Fig. 3, A and D) showed, as would be expected from
the data presented in Fig. 2
, some loss of the CFSE label, while donor
Thy-1.1+ cells in the BAL had clearly cycled more
than once (Fig. 3, C and F).
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, I and L) and enhanced
turnover in both the BAL and spleen (Fig. 3, I,
L, G, and J). However, no donor
DbNP366+ T
cells were found at this time point in the MLN (Fig. 3, H
and K), and the total number of donor
DbNP366+ T
cells in the spleen was no greater than in the uninfected controls
(Fig. 3, A and G). The counts in the BAL had
increased; however, while the CD8+ set dominates
(75%) the lymphocyte population in this site of inflammatory
pathology, there are still less donor
DbNP366+ T
cells in the BAL than the spleen (see legend to Fig. 3).
Evidence of a recall T cell response was apparent for the spleen, MLN,
and BAL populations of mice that had been given both donor
DbNP366+ T
cells and the HKx31 virus i.n. 13 days previously (Fig. 3, M–O). Most, but not all, of these virus-specific
CD8+ T cells had lost the CFSE label (Fig. 3, P–R), indicating that they had undergone at least six
cycles of cell division subsequent to transfer. There were also
substantial numbers of donor
DbNP366+ T
cells at every site sampled (Fig. 3, M–O). Thus, the
adoptively transferred
DbNP366+ memory
population clearly responded to the HKx31 challenge.
Comparison of the recall and primary CD8+ T cell responses in memory and naive mice
Further dissection of the secondary donor
DbNP366+ T
cell response was measured by staining for tetramer and Thy-1.1 various
times after infection in different sites. Significant numbers of donor
DbNP366+ T
cells had localized to the spleen, MLN, and BAL by day 5 after
respiratory challenge with the HKx31 virus (Fig. 4, A, G, and
M). At this stage, the donor
DbNP366+ T
cells isolated from BAL and MLN have proliferated to a greater extent
than those found in the spleen (Fig. 4, D, J, and
P), while there was no evidence of a significant host
(Thy-1.1-)
DbNP366+
response in either these mice (Fig. 4, A, G, and
M).
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, B,
H, and N), and evidence of clonal expansion was
even more apparent on day 10 for both the
Thy-1.1+ donor and Thy-1
host.1-DbNP366+
sets (Fig. 4, C, I, and O). A few
CFSEhigh lymphocytes were still found in the
spleen and BAL on days 7 and 10 (Fig. 4, E, F,
Q, and R), suggesting that some of the
transferred donor
DbNP366+ T
cells contributed minimally to the rapid cell expansion (Fig. 4, B, C, N, and O) observed
during the secondary influenza-specific CD8+
response (23). These residual
CFSEhigh donor
DbNP366+ T
cells were not found in the MLN (Fig. 4, K and
L), emphasizing the importance of the regional lymph nodes
in this secondary response.
The absolute numbers of
CD8+DbNP366+
and
CD8+DbPA224+
T cells found in the spleen, MLN, and BAL on days 5, 7, and 10 are
shown in Fig. 5. There were increased
numbers of
CD8+DbNP366+-specific
T cells in mice that received donor
DbNP366+ T
cells in the BAL at all times tested. The spleen had increased numbers
on day 7, but this difference was no longer apparent by day 10.
Surprisingly, concurrent analysis of the recall and naive response to
the HKx31 virus revealed that greater numbers of
CD8+DbPA224+
T cells were generated in the B6 Thy-1.2+ mice
that were given the donor
DbNP366+
memory T cells compared with B6 Thy-1.2+ controls
(Fig. 5). This was seen in the spleen and BAL on day 7, and in the
spleen, BAL, and MLN on day 10. Interestingly, there were fewer
tetramer-specific CD8+ T cells in the MLN on day
7 in mice that received donor
DbNP366+
compared with the B6 controls. Flow cytometric analysis confirmed that
the
CD8+DbPA224+
set observed on day 10 was uniformly Thy-1.2+
(Fig. 6), ruling out the possibility that
this lymphocyte population was in some way emerging from the
transferred donor
DbNP366+
set.
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and 5 was repeated twice more,
with similar results on each occasion. These findings are summarized as
ratios in Table I, which presents the
data for individual spleens and three pools of BAL and MLN from a total
of 15 mice. Although the donor (Thy-1.1) and naive (Thy-1.2)
CD8+DbNP366+
T cells are present at comparable prevalence in the spleen on day 10,
there were more donor
DbNP366+ T
cells in the MLN on days 7 and 10 and the BAL on day 10
(Thy-1.1/Thy-1.2, Table I). However, while the numbers of host
DbNP366+ T
cells were essentially equivalent (or a little lower) in the memory vs
the naive mice (Table I), the counts for the
Thy-1.2+CD8+DbPA224+
set were significantly enhanced in all but the day 7 MLN for those that
had been given the immune donor
DbNP366+ T
cells (Table I).
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Viral lung homogenates of naive B6 mice were compared with mice
that received donor
DbNP366+ T
cells on days 5, 7, and 10 after infection with HKx31. Although small
in numbers (Figs. 4 and 5), the donor
DbNP366+
effectors in the respiratory tract of the memory mice on day 5 were
sufficient to cause a significant reduction in lung virus titers (day
5, Fig. 7, p < 0.03). On
day 7, substantial numbers of virus-specific cells detected correlated
with a 100-fold reduction in virus titers (Fig. 5). Clearance of
virus from the lung was complete by day 10.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Why should a secondary response to
DbNP366 promote greater
clonal expansion of naive CD8+ T cells specific
for DbPA224, but not for
DbNP366? Interestingly, on
day 7, there were fewer
DbNP366+
and DbPA224 T cells
detected in the MLN of mice that had received donor
DbNP366+ T
cells compared with the B6 controls. The presence of memory cells may
in some way cause specific CD8+ T cells to track
to the site of infection faster, possibly due to the earlier production
of inflammatory mediators and chemokines. Although more rapid
differentiation to effector function of the transferred
CD8+DbNP366+
memory T cells may enhance the production of cytokines/chemokines
(23, 24) that facilitate the recruitment of naive
precursors to the lymphoid tissue and to the site of virus-induced
pathology in the lung, this effect should be equally apparent for the
recipient DbPA224- and
DbNP366-specific
populations. Perhaps IFN- produced by the
CD8+DbNP366+
memory T cells (25) induces enhanced expression of the
DbPA224, but not the
DbNP366, epitope.
A further possibility is that the CD8+DbNP366+ and CD8+DbPA224+ responses are fundamentally different. Although both populations show strong CTL activity for peptide-pulsed EL4 (H-2b) targets, only the CD8+DbNP366+ set is lytic for virus-infected EL4 cells (data not shown). Transfer of OT-1 TCR transgenic CD8+ T cells inhibited the host response to immunodominant and subdominant epitopes due to competition for these peptides presented on the same APC (26). Although it seems unlikely that the DbNP366 and DbPA224 epitopes would be expressed on separate sets of APCs, it remains a possibility. Although we do not know that an equivalent situation applies for productively infected lung epithelium, or for dendritic cells in which the virus undergoes a defective growth cycle, is it possible that cells replicating the virus are neither stimulators nor targets in the DbPA224-specific response? Perhaps apoptotic virus-infected cells that are phagocytosed by dendritic cells (27, 28) present DbPA224 subsequent to processing of the PA224–233 peptide via an alternative pathway (29). Lysis mediated by the donor DbNP366+ CTL effectors could potentiate this cross-priming effect (30). A further implication of the cross-priming model is that the response to DbPA224 may be irrelevant to clearance of the influenza A viruses, and could even be inhibitory by removing a population of stimulators that also express the DbNP366 epitope.
Kinetic analysis indicated that the adoptively transferred
CD8+DbNP366+
memory set cycled at a steady rate in naive, congenic mice that had not
been exposed to virus. This is quite different from the profile that we
found previously (2) when mice were fed the thymidine
analogue bromodeoxyuridine (BrdU) during the course of a secondary
(HKx31
PR8) response, then chased for several months to determine the
rate of loss of the BrdU label from the
CD8+DbNP366+
T cells. Although some of these lymphocytes were clearly cycling at
rates equivalent to those found in the present CFSE-staining
experiments, many remained BrdUhigh for months.
Challenge with a third, H7N7 influenza A virus induced only a
proportion of this massive
CD8+DbNP366+
set to divide further.
One difference is that the
CD8+DbNP366+
T cells were present at 
10-fold higher frequency in the secondary
challenge studies than in the present adoptive transfer experiments. Is
it the case that a large memory T cell population will divide less than
a small one? Even so, there is no obvious reason that memory
CD8+ T cells specific for one particular epitope
should have any special relationship once the inducing Ag has been
eliminated (31, 32). How could an individual
CD8+ memory T cell sense that it is part of an
epitope-specific set of a particular size? Perhaps most of the
nondividing
CD8+DbNP366+
T cells were simply lost on cell transfer, although a few
CFSEhigh
CD8+DbNP366+
T cells were found following virus challenge. Given that the
proliferating T cells go through at least six cycles of cell division
before extinction of the CFSE label, this small set of
CFSEhigh
CD8+DbNP366+
T cells would have been a much more substantial component in the
original population.
Although these adoptive transfer studies established a population
of Thy-1.1+
CD8+DbNP366+
memory T cells in the naive Thy-1.2+ recipients
that seemed (at least numerically) to be equivalent to that found
following primary exposure to the PR8 virus, the secondary response
following respiratory HKx31 virus infection did not seem to be as rapid
or as large as that associated with the simple HKx31PR8 challenge
(2, 7, 15, 18). An obvious difference between the adoptive
transfer and PR8-priming approaches is the absence of established
CD4+ T help specific for peptides from conserved,
internal proteins shared by the HKx31 and PR8 viruses
(33, 34, 35). Also, previous experiments have not looked at
the functional capacity of CD8+ T cells expanded
by four, successive exposures to viruses carrying the same peptide.
Both the evidence of early virus titer reduction and the substantial
cell division following the final HKx31 challenge would suggest that
these CD8+ T cells are behaving normally, but,
given the possible implications for vaccine development, it may be
appropriate to look more closely at the quality of such responses in
future experiments.
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Acknowledgments |
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Footnotes |
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2 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. E-mail address: peter.doherty{at}stjude.org
3 Abbreviations used in this paper: HKx31, A/Hong Kongx31 (H3N2) influenza A virus; BAL, bronchoalveolar lavage; B/HK, B/Hong Kong influenza B virus; BrdU, bromodeoxyuridine; EID50, 50% egg infective dose; i.n., intranasal; MLN, mediastinal lymph node; NP, influenza nucleoprotein; PA, influenza acid polymerase; PR8, A/Puerto Rico/34 (H1N1) influenza A virus; VV-NP, vaccinia virus NP.
Received for publication March 30, 2001. Accepted for publication June 25, 2001.
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A. D. Hislop, N. E. Annels, N. H. Gudgeon, A. M. Leese, and A. B. Rickinson Epitope-specific Evolution of Human CD8+ T Cell Responses from Primary to Persistent Phases of Epstein-Barr Virus Infection J. Exp. Med., April 1, 2002; 195(7): 893 - 905. [Abstract] [Full Text] [PDF]
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0.02). The experimental protocol is described
in the legend to Fig. 1
) and Thy-1.2 mice that had been given the donor
DbNP366+ memory T cells (
). The
recipients were infected i.n. with the HKx31 virus 2 days after cell
transfer, then sampled after a further 5, 7, or 10 days. The numbers on
the y-axis were calculated from the percentage of cells
staining with the CD8-Tricolor and
PE-DbNP366+ or
PE-DbPA224+ reagents and the viable
cell counts. The data presented here are representative of three
separate experiments.
