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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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assay has led to the
identification of a new immunogenic peptide (SSYRRVPGI) from the
influenza PB1 polymerase (PB1703–711) and a mimotope
(ISPLMVAYM) from the PB2 polymerase (PB2198–206).
CD8+ T cells specific for KbPB1703
make both IFN- and TNF-
following stimulation with both peptides.
The CD8+ KbPB1703+
population kills PB2198-pulsed targets, but cell lines
stimulated with PB2198 neither bind the
KbPB1703 tetramer nor become CTL. This
CD8+KbPB1703+
population is prominent in the primary response to an H3N2 virus,
although it is much less obvious following secondary challenge of
H1N1-primed mice. Even so, we can now account for >40% of the
CD8+ T cells in a primary influenza pneumonia and >85% of
those present after H3N2 
H1N1 challenge. Profiles of IFN- and
TNF- staining following in vitro stimulation have been traced for
the four most prominent influenza peptides through primary and
secondary responses into long-term memory. The
DbNP366 epitope that is immunodominant after
the H3N2 H1N1 challenge shows the lowest frequencies of
CD8+ IFN-+TNF-+ cells for >6
wk, and the intensity of IFN- staining is also low for the first 3
wk. By 11 wk, however, the IFN-/TNF- profiles look to be similar
for all four epitopes. At least by the criterion of cytokine
production, there is considerable epitope-related functional diversity
in the influenza virus-specific CD8+ T cell response. The
results for the KbPB1703 epitope and the
PB2198 mimotope also provide a cautionary tale for those
using the cytokine staining approach to identity antigenic
peptides. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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subsequent to short-term stimulation with
peptide to cause cytokine production
(PepC)4 assay, has greatly
facilitated the dissection of cell-mediated immunity of
H-2b mice infected with the influenza A viruses
(3). Quantitative analysis has focused on the primary and
recall CD8+ T cell responses in the regional mediastinal
lymph nodes (MLN), the spleen, and the pneumonic lung sampled by
bronchoalveolar lavage (BAL). The secondary challenge experiments rely
on the fact that the surface hemagglutinin (H) and neuraminidase (N)
glycoproteins of the A/Aichi/68/HKx31 (H3N2), and A/PR/8/34 (PR8,
H1N1) influenza A viruses are sufficiently different to avoid any
cross-neutralization with antibody (4), while these two
viruses share the internal components that provide allof the peptides
recognized to date by influenza-specific,
H-2b-restricted CD8+ T cells
(5, 6, 7). Productive infection is essentially limited to the
lung, reflecting that a protease required to cleave the influenza virus
H molecule is restricted in distribution to the respiratory epithelium
(8). The influenza mouse model thus provides an optimal
experimental system for the quantitative analysis of CD8+ T
cell responsiveness in a localized infection (9, 10).
The primary CD8+ T cell response following intranasal
(i.n.) challenge with the HKx31 virus is largely specific for two
peptides derived from the viral nucleoprotein (NP366–374)
and the PA polymerase (PA224–233), respectively
(7). Both are presented by H-2Db. The
CD8+DbNP366+ and
CD8+DbPA224+ sets
detected by tetramer staining comprise <5% of the CD8+ T
cells in spleen and >30% of those recovered by BAL from the infected
lung. The secondary response (HKx31 PR8) is dominated by the
CD8+DbNP366+
population, although the
CD8+DbPA224+ T cells
also increase in prevalence.
The present experiments identify another epitope that is prominently
recognized in the primary response to the HKx31 influenza A virus.
These same T cells also make both IFN- and TNF- (11)
following stimulation with a totally different peptide derived from
another influenza virus protein, although this mimotope does not seem
to stimulate an independent immune response. Any assignment of
antigenicity based on screening with the PepC assay must clearly be
confirmed by other, more functional criteria.
Patterns of IFN- and TNF- staining have also been analyzed for a
spectrum of immunogenic peptides in both the acute response and in
long-term memory. The cytokine expression profiles for
influenza-specific CD8+ T cells are clearly a function of
the particular epitope, the level of local antigen stimulation, and the
time that has elapsed since primary or secondary challenge. These
observations raise intriguing questions about possible selective loss,
or further differentiation with time, in Ag-specific CD8+
memory T cell populations.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Female C57BL/6J (B6, H-2b) mice were purchased from The Jackson Laboratory (Bar Harbor, ME). Mice that were at least 8 wk of age were anesthetized by i.p. injection with avertin (2,2,2-tribromoethanol) and infected i.n. with 106.8 50% egg infectious doses of the HKx31 influenza A virus (3, 12). "Memory" mice for secondary challenge experiments were injected i.p. at least 6 wk before with 108.5 50% egg infectious doses of the PR8 influenza virus. The PR8 and HKx31 influenza A viruses (4) have different surface H and neuraminidase (N) glycoproteins (H1N1 and H3N2, respectively), but share internal components (NP, NS1, NS2, M, PA, PB1, PB2). At the time of sampling, the mice were anesthetized and exsanguinated from the axillary artery. Lymphocytes were obtained from the pneumonic lung (12) by BAL, and adherent cells were removed by incubating on plastic for 1 h at 37°C. Spleen and MLN samples were disrupted and enriched for CD8+ T cells by incubation with mAbs to CD4 (GK1.5) and MHC class II glycoprotein (M5/114.15.2), followed by magnetic depletion subsequent to binding anti-rat and anti-mouse Ig-coated beads (Dynal, Oslo, Norway).
PepC intracellular cytokine assay
The PepC assay utilized lymphocytes that were 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 recombinant IL-2,
and 5 µg/ml brefeldin A (Epicentre Technologies, Madison, WI) in the
presence or absence of viral peptide (7). They were then
washed and stained with anti-mouse CD8-FITC Ab (BD Pharmingen,
San Diego, CA). Nonspecific Fc binding was blocked using anti-mouse
CD16/32 (BD 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 (30 min) with conjugated mAbs to IFN- (PE-XMG 1.2)
and/or TNF- (APC-MP6-XT22). The mAbs to IFN- and TNF- were
mixed. The specificity of the staining reaction was checked initially
by blocking with excess, purified cytokine and by the use of isotype
control Ab. 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 percent CD8+IFN-+ or
CD8+TNF-+ without peptide (<0.2%) was
subtracted from the percent CD8+IFN-+ or
CD8+TNF-+ with peptide to give the percent
specific CD8+ T cells staining for the particular cytokine.
Kinetic analysis of epitope-specific CD8+ T cell
populations recovered directly ex vivo utilized 1 µM viral
peptide.
Influenza epitopes
The influenza A virus peptides were synthesized at the Center
for Biotechnology, St. Jude Children’s Research Hospital, using a
model 433A peptide synthesizer (Applied Biosystems, Berkely, CA) and
purified by HPLC. The previously identified
(5, 6, 7) peptides/epitopes were:
DbNP366, H-2Db +
NP366–374; DbPA224,
H-2Db + PA224–233;
KbNS2114, H-2Kb +
NS2114–121, KbM1128, and
H-2Kb + M1128–135. In addition, a new
epitope (KbPB1703, H-2Kb +
PB1703–711) and a mimotope (PB2198–206) were
identified by screening (at 10 µM) immune spleen cells with a panel
of overlapping 15-mer peptides spanning the PB1 and PB2 proteins of the
PR8 virus (13) using the PepC assay for IFN-. The
positives were resynthesized as shorter sequences (9–10 aa). The
restriction element for the new PB1 peptide was identified using the
RMAS peptide stabilization assay. The RMAS cells (14) were
first incubated for 16 h at 26°C in complete medium, then in
96-well plates in the presence of 2-fold dilutions of peptide (100 µM
to 760 pM) for 30 min at room temperature followed by 3 h at
37°C. The cells were then stained with mAbs to H-2Db
(28.14.85) or H-2Kb (AF6.88.5.3), followed by
FITC-conjugated rabbit anti-mouse IgG (Dako, Copenhagen, Denmark),
and analyzed by flow cytometry.
Tetramer staining of peptide-specific CD8+ T cells
Virus-specific CD8+ T cells were identified using
tetrameric complexes (1, 3, 7) of the H-2Db
glycoprotein and peptides derived from the NP ASNENMETM
(5) and polymerase 2 protein (PA) SSLENFRAYV, or
H2Kb + SSYRRPVGI from PB1. These are referred to in
the text as the DbNP366,
DbPA224, and KbPB1703
tetramers. Recombinant H-2Db or H-2Kb molecules
with a birA biotinylation motif substituted for the
carboxyl-terminal transmembrane domain were refolded with human
2-microglobulin plus the appropriate viral peptide,
biotinylated with birA and complexed at a 4:1 molar ratio
with neutravidin-PE (Molecular Probes, Eugene, OR). Lymphocytes were
stained for 60 min at room temperature with the tetrameric complexes in
PBS/BSA/azide, followed by staining with anti-CD8-FITC, washed
twice, and analyzed by flow cytometry.
Cell lines and CTL assays
Polyclonal cell lines were generated from mice infected acutely with the HKx31 virus. Irradiated (3000 rad) HKx31-infected naive spleen cells were washed twice and incubated (106/ml) with responder lymphocytes (1.5 x 106/ml) for 5–7 days in complete medium at 37°C with 5% CO2. The cell lines were then generated by multiple cycles of restimulation with peptide-pulsed (1 µM) irradiated spleen cells every 5–7 days in medium incorporating 10 U/ml IL-2.
The EL4 (H-2b) target cells were labeled with Na51Cr for 1 h, pulsed with viral peptides or infected with the HKx31 influenza A virus for 60–90 min, washed twice, and plated at 5000 targets/well. They were then 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 X-100-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 X-100). The level of 51Cr release from targets incubated in the absence of T cells did not exceed 15% of the total Triton X-100-mediated 51Cr release.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Overlapping 15-mer and 10-mer peptides were made (15)
for the PR8 influenza PB1 and PB2 proteins, screened at 10 µM in the
PepC assay for IFN- synthesis, and then tested for up-regulation of
MHC class I molecules in TAP-2-deficient RMAS cells (Fig. 1
). A PB1 epitope was identified as a
H-2Kb-restricted 9-aa (SSYRRPVGI;
KbPB1703–711) sequence which loosely conforms
to the defined H-2Kb motif (16)
XXYXF/YXX(X)L/M/I/V. A second stimulatory peptide was identified in PB2
(ISPLMVAYM; PB2198–206) by the PepC assay. However, it was
not possible to assign this PB2198 peptide to either
H2Kb or H2Db. No specific cytolysis above
background was detected when PB2198-pulsed L-929 cells
transfected with H-2Db or H-2Kb molecules were
used as targets (data not shown), and only high concentrations of
peptide enhanced the expression of both MHC class I glycoproteins in
the RMAS assay (Fig. 1).
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). Cell lines were then generated by six
cycles of restimulation with the PB1703 or
PB2198 peptides and assayed for CTL activity. The
PB1703 lines were lytic for EL4 cells pulsed with
PB1703–711, PB2198–206, and the truncated
PB1703–710 (Fig. 3A), although
PB1703–710 showed little capacity to up-regulate
H-2Kb expression in the RMAS assay (Fig. 1
). The
PB2198 lines, however, showed minimal evidence of CTL
activity (Fig. 1A). In addition, the PB2198
lines were less uniformly CD8+ (Fig. 3B),
although this phenotype only emerged after three cycles of in vitro
culture (data not shown), and did not stain with the
KbPB1703 tetramer (Fig. 3C).
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(Fig. 4, C and
D) were indeed distinct sets
of T cells. The BAL cells were stained with the
KbPB1703 tetramer, sorted into
CD8+KbPB1703+ and
CD8+KbPB1703- sets,
and then stimulated with the two epitopes together (Fig. 4, J and O) or separately (Fig. 4, H,
M, I and N). It was very obvious that
the PB2198 peptide was indeed stimulating the majority of
the CD8+KbPB1703+ T
cells (Fig. 4 IN). The only significant response in the
CD8+KbPB1703-
population was caused by the control DbNP366
peptide (Fig. 4G). It thus seems reasonable to assume that
PB2198 (although completely unrelated in sequence) is a
mimotope that can stimulate an IFN- response by highly activated
PB1703-specific CD8+ T cells (Fig. 4) and is
recognized by PB1703-specific CTL (Figs. 2 and 3A), but is not capable of driving either the clonal
expansion of cells that bind the
KbPB1703- tetramer or effector CTL
generation following in vitro culture (Fig. 3, A and
C).
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Immunologically naive (primary) and PR8-primed mice (secondary)
were challenged i.n. with the HKx31 virus, then analyzed by the
PepC/IFN- assay for the number of CD8+ T cells
responding to five different H-2b-restricted epitopes (Fig. 5). In looking at Fig. 5, it is important
to realize that the y-axes differ for the various panels. We
chose to express the results as numbers rather than percent values, as
this was the only way that the response profiles for the different
epitopes and anatomical sites could be adequately illustrated.
Following primary challenge, the KbPB1703
peptide was found to rank third (after DbNP366
and DbPA224) in magnitude for the response in
the lymphoid tissue (Fig. 5, A and B) and
was also prominent in the BAL (Fig. 5C). The recall response
was, as shown previously by concordant patterns of staining with both
tetramers and the PepC/IFN- assay (3, 7), dominated by
the expansion of the DbNP366-specific set (Fig. 5, D–F). Although the secondary
DbNP366-specific response was increased (Fig. 5, D–F) 10- to 15-fold above that found in the primary
(Fig. 5, A–C), the difference in magnitude for the
subdominant epitopes tended to be more in the range of 2- to 4-fold
(Fig. 5, A–C and G–I). Adding the percent
values (data not shown) used to calculate the data presented in Fig. 5
also established that influenza-specific T cells account for >40% of
the CD8+ T cells that localize to the lungs of mice with a
primary influenza virus pneumonia, with that value increasing to >85%
after secondary challenge.
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and TNF- production
The next question was whether the PB1703 epitope and
the PB2198 mimotope would trigger the same spectrum of
TNF- and IFN- staining (PepC assay) in the CD8+ T
cell population recovered by BAL from the site of virus-induced
pathology. The TNF-/IFN- profiles were essentially similar
following exposure to the PB1703 and PB2198
peptides, but the spectrum for the NP366 peptide was
different (Fig. 6). Approximately 40% of
the IFN--producing, DbNP366-specific
CD8+ T cells were not producing TNF-. In addition, a
small fraction (<5%) of DbPA224-specific
CD8+ T cells produced low levels of IL-2 (data not shown)
while no DbNP366-specific CD8+ T
cells appeared to secrete this cytokine.
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) to
the four principle influenza CD8+ T cell epitopes (see Fig. 5). More CD8+IFN-+/TNF-+ than
CD8+IFN-+TNF-- spleen cells
were found for the KbNS2114,
DbPA224-, and
KbPB1703-specific sets on day 8 after secondary
challenge (Fig. 7). The exception was the splenic
DbNP366-specific population, although the
majority of the
CD8+DbNP366-specific T cells in the
BAL were IFN-+/TNF-+ at the same time
point (Fig. 7). The difference is likely to reflect that the levels of
DbNP366 encountered in the lung, the site where
the virus is replicating, are much higher than those in the spleen.
Previous experiments have shown very clearly that potent CTL effector
function is most obvious in the BAL population. By day 21 after the
H3N2 H1N1 challenge, the majority of both the BAL and the splenic
CD8+DbNP366-specific T cells were
IFN-+/TNF-+.
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+/TNF-+ by day 12 after primary
infection, and retained that profile as both memory T cells (Fig. 8A, day 30, and day 0
B) and in the long-term following secondary challenge (Fig. 8, A–D). This was also true for the secondary, but not the
primary, response in the BAL to DbNP366 (Fig. 8, C and D). Long-term memory following both
primary and secondary challenge was characterized by a slow shift of
the CD8+DbNP366+ T
cells toward an IFN-+/TNF-+
phenotype.
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profiles were essentially similar for the
KbNS2114-,
DbPA224-, KbPB1703-,
and DbNP366-specific sets on days 8 and 30 of
the primary response (Fig. 9A). However, the massive
expansion (Fig. 5, D–F) of the
CD8+DbNP366-specific T cell
population that occurs during the secondary response was characterized
by a much lower level of IFN- staining (Fig. 9C, days 8
and 21). This effect was no longer apparent for the memory T cells
recovered on day 78 after secondary challenge (Fig. 9C, day
78) and was not obvious for TNF- production in either the primary or
secondary response. Clearly, the patterns of cytokine response can vary
for different epitopes, at least for the first 1–2 mo, after a primary
or secondary encounter with an influenza A virus (Figs. 8 and 9).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and TNF-.
However, PB2198 neither promotes clonal expansion of the
CD8+KbPB1703+ set nor
generates CTL effectors specific for targets pulsed with either the
PB1703 or PB2198 peptides. At the other end of
the spectrum, the prominent DbNP366-specific
response is characterized by levels of IFN- and TNF- production
that are low relative to those induced by
KbPB1703 and DbPA224.
Although DbNP366 drives lymphocyte
differentiation and proliferation very efficiently in vivo, there is no
evidence that PB2198 is ever expressed on the surface of
either virus-infected targets or Ag-presenting stimulator cells. What
useful generalizations be drawn from these findings?
The results with the PB2198 mimotope provide several
lessons. The first is the very practical point that, although the
PepC/IFN- assay allows the rapid identification of potentially
immunogenic peptides, this can only be regarded as a screening
procedure. Any such assignment of antigenicity must be confirmed by
other functional criteria. The second is that there is no a priori
mechanism for identifying possible cross-reactivities: the relationship
between ISPLMVAYM and SSYRRPVGI is defined only by a spectrum of the
TCRs that are responding to the KbPB1703
epitope. The third is that the profiles of cytokine production
identified subsequent to stimulation with PB2198 must be
those that are established by the initial stimulation with
KbPB1703. A low-affinity-avidity interaction
(17) between KbPB2198 and the
KbPB1703-specific TCRs will then cause IFN-
and TNF- production, but cannot drive clonal expansion or CTL
generation. The implication is that different functions are set at
different thresholds. The triggering of a particular response is
presumably determined by the avidity of the TCR-epitope interaction
that in turn dictates the magnitude of signal
(18, 19, 20).
It is intriguing that the lowest level of concordance for IFN- and
TNF- production is detected throughout for the
DbNP366-specific population that is so
prominent in the secondary H3N2 H1N1 response (3, 7). Perhaps DbNP366 is selecting for the
development of memory T cells with a much broader range of TCR
affinities. We know, for example, that both the acute and memory
CD8+ T cell responses to DbPA224
utilize predominantly the V7.1 TCR chain (21). Although
V8.3 tends to be expressed on 30–60% of the
DbNP366-specific T cells (22), the
pattern is much less consistent than that for
DbPA224 and V7.1. Although the impression to
date is that the percent of V8.3+ T cells in the
DbNP366-specific set does not change with time,
it would be necessary to look sequentially within individuals to see
whether there is a progressive focusing of TCR clonotypes as this
T cell population evolves toward the "memory"
IFN-+TNF-+ phenotype
(23).
Another possibility is that the generation of high levels of TNF-
following a primary encounter with Ag is correlated with the
development of less responsive or diminished (24, 25, 26)
memory T cell populations. The primary response to
DbPA224 is initially higher than that to
DbNP366 though, by day 12 after i.n. challenge,
there are larger numbers of DbNP366-specific T
cells in the spleen. Proportionally more of these
DbPA224-specific T cells are producing TNF-.
The nature of both the primary and secondary CD8+ T cell
response to these two epitopes should be compared for mice that are not
capable of making, or responding to TNF-. We also need to re-examine
the situation for H-2kxb F1 mice
(21), where the
CD8+DbNP366-specific response is
not immunodominant following the secondary H3N2 H1N1 challenge.
Will decreasing the size of the
DbNP366-specific population modify the profile
of cytokine expression, or is this a function of the TCR-epitope
interaction?
The results presented here are generally in accord with the observation
of Slifka and Whitton (11) that lymphocytic
choriomeningitis virus-specific,
CD8+IFN-+TNF-+
double-positive cells are more prominent in the established memory T
cell pool than in activated CD8+ T cell populations
recovered during the acute Ag-driven phase of the response. The results
from the influenza model add the insight that the extent of this effect
differs for particular peptides. The secondary CD8+
DbPA224+ response shows the
characteristic IFN-+TNF-+ memory profile
identified by Slifka and Whitton (11). This is also true
for the CD8+DbNP366+
set in the BAL, but not for the comparable population detected in the
spleen following the H3N2 H1N1 challenge. The difference probably
reflects that the higher level of antigenic stimulation in the lung
(12) is driving the emergence of the
IFN-+TNF-+ phenotype.
Perhaps the
CD8+DbNP366+IFN-+TNF-+
set that predominates with time is the "true" memory population
(27). Both tetramer staining and the PepC assay
demonstrate that
CD8+DbNP366-specific T cells are
present in the memory T cell pool at an order of magnitude higher
(2, 3) than the frequencies determined by earlier
(28) limiting dilution analysis. This difference may
reflect that only 10% of the
CD8+DbNP366+ set
survives the 12–15 cycles of cell division required to read-out as
positive in the limiting dilution analysis CTL assay (27),
although all can apparently cycle to some extent after secondary in
vivo stimulation (29). The differences in cytokine
profiles presented here suggest that the spectrum of functional
diversity may be much greater for the massive
DbNP366+ population generated
following the H3N2 H1N1 challenge than for the more modest
secondary response to, for example, DbPA224. It
is obviously important to clarify whether the characterization of an
epitope as "dominant" or "subdominant" (30) based
on the comparison of T cell numbers (21) is indeed
reflective of functional efficacy in the in vivo situation.
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Acknowledgments |
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Footnotes |
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2 Current address: The Walter and Eliza Hall Institute of
Medical Research, Parkville 3050, Australia.
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: PepC, peptide/cytokine; BAL, bronchoalveolar lavage; H, hemagglutinin; HKx31, the A/Aichi/68/HKx31 H3N2 influenza A virus; M1, viral matrix protein; N, neuraminidase; NP, nucleoprotein; NS2, viral nuclear export protein; PA, PB1 and PB2, the three influenza virus polymerase proteins; PR8, the A;/PR/8/34 H1N1 influenza A virus; i.n., intranasal; MLN, mediastinal lymph node.
Received for publication November 20, 2000. Accepted for publication January 23, 2001.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and 
T cell subsets in viral immunity. Annu. Rev. Immunol. 10:123.[Medline]
8.3 T cells in the H-2Db-restricted response to an influenza A virus nucleoprotein epitope. J. Immunol. 151:2658.[Abstract]
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 G. T. Belz, L. Zhang, M. D. H. Lay, F. Kupresanin, and M. P. Davenport Killer T cells regulate antigen presentation for early expansion of memory, but not naive, CD8+ T cell PNAS, April 10, 2007; 104(15): 6341 - 6346. [Abstract] [Full Text] [PDF]
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S. Lee, S. A. Miller, D. W. Wright, M. T. Rock, and J. E. Crowe Jr. Tissue-Specific Regulation of CD8+ T-Lymphocyte Immunodominance in Respiratory Syncytial Virus Infection J. Virol., March 1, 2007; 81(5): 2349 - 2358. [Abstract] [Full Text] [PDF]
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P. G. Thomas, S. A. Brown, R. Keating, W. Yue, M. Y. Morris, J. So, R. J. Webby, and P. C. Doherty Hidden Epitopes Emerge in Secondary Influenza Virus-Specific CD8+ T Cell Reponses J. Immunol., March 1, 2007; 178(5): 3091 - 3098. [Abstract] [Full Text] [PDF]
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J. Stambas, P. C. Doherty, and S. J. Turner An In Vivo Cytotoxicity Threshold for Influenza A Virus-Specific Effector and Memory CD8+ T Cells J. Immunol., February 1, 2007; 178(3): 1285 - 1292. [Abstract] [Full Text] [PDF]
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D. O. Co, L. H. Hogan, J. Karman, E. Heninger, S. Vang, K. Wells, Y. Kawaoka, and M. Sandor Interactions between T Cells Responding to Concurrent Mycobacterial and Influenza Infections J. Immunol., December 15, 2006; 177(12): 8456 - 8465. [Abstract] [Full Text] [PDF]
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B. P. Lawrence, A. D. Roberts, J. J. Neumiller, J. A. Cundiff, and D. L. Woodland Aryl Hydrocarbon Receptor Activation Impairs the Priming but Not the Recall of Influenza Virus-Specific CD8+ T Cells in the Lung J. Immunol., November 1, 2006; 177(9): 5819 - 5828. [Abstract] [Full Text] [PDF]
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