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Department of Microbiology and Immunology, Kimmel Cancer Institute, Thomas Jefferson University, Philadelphia, PA 19107
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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ELISPOT analysis following priming with viruses
expressing low, high, or excessive epitope levels. The size of the
epitope-specific CD8+ T cell memory population correlates
with Ag dose at the low and high levels of epitope expression. However,
at excessive epitope levels, the number of functional,
IFN--producing, epitope-specific memory cells is significantly
reduced compared with the number of tetramer+ cells. These
results demonstrate that the level of epitope expressed during an acute
viral infection in vivo can dramatically influence CTL memory size.
Furthermore, when epitope is overexpressed, the quality of the response
can be adversely affected. Therefore, epitope expression level is an
important consideration when developing approaches to optimize CTL
memory induction. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Evidence suggests that the size and quality of a virus-specific memory CTL population can significantly influence the ability to control a secondary infection. First, adoptive transfer experiments have shown that low numbers of memory cells are less effective than high numbers in the control of virus replication or protection from lethal challenge (5, 6). Second, an elevated frequency of prechallenge, vaccine-induced CTL correlates strongly with greater viral control upon SIV challenge in macaques (7). In addition to the size of the virus-specific memory T cell pool, the quality of those cells can also influence their effectiveness. Memory CTLs specific for different viral epitopes provide distinct levels of protection upon secondary challenge (6, 8). Finally, T cell avidity may influence memory T cell effectiveness because high avidity CTL lines mediate greater protection from challenge than low avidity CTLs (9).
Because of the potential impact on memory T cell effectiveness, it is important to investigate how memory T cell populations are shaped quantitatively and qualitatively. Limiting dilution studies following Sendai virus infection have demonstrated that the size of the peak antiviral CTL population correlates with the size of the resulting memory pool (10). Furthermore, the relationship between the size of the peak and memory populations holds for dominant and subdominant epitopes regardless of the absolute magnitude of the individual responses (1). This suggests that the size of the peak antiviral T cell population influences, or is at least a predictor of, the size of the resulting memory pool. In addition to quantitative characteristics, the quality of memory CTLs is also determined early in the primary response since the TCR repertoire of epitope-specific cells at the peak and in the memory pool is similar (11, 12). These studies highlight the importance of understanding how various components of primary antigenic stimulation will impact Ag-specific T cell memory.
Recently, we (13) and others (14) have examined the influence of the level of epitope expressed during in vivo CTL priming on the magnitude of the initial epitope-specific CTL population. Epitope expression levels dramatically influence the magnitude of the initial responding epitope-specific CTL population since graded primary epitope-specific T cell responses are generated over a wide range of epitope levels (13, 14). Interestingly, these studies also showed that the maximal T cell response was achieved at submaximal levels of epitope expression (13, 14). However, the influence of epitope levels on the development of memory T cell populations was not examined in earlier experiments. In the present study we examine the induction of epitope-specific CTL memory in response to a range of epitope expression that exceeds 75-fold in the face of a constant level of vaccinia virus (VV)5 infection. Using this system of variable Ag expression, we have investigated the influence of epitope expression level during initial CTL priming on the size of the epitope-specific CTL memory pool. Our results demonstrate that, for a given epitope, low or high levels of peptide availability during the initial CTL expansion result in correspondingly small or large epitope-specific memory populations. However, an excessive level of epitope expression does not yield an increase in memory size over that achieved at high levels of epitope and results in a qualitatively inferior memory CTL population.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Six to 8-wk-old female C57BL/6 mice were purchased from Taconic Laboratories (Albany, NY) and maintained in the Thomas Jefferson University Animal Facilities (Philadelphia, PA). The murine fibroblast cell line L929 transfected with the Kb gene (L-Kb, H-2Kb-expressing) cells; kindly provided by Dr. Y. Patterson, University of Pennsylvania, Philadelphia, PA) and 143B Hu TK- cells (CRL 8303; American Type Culture Collection, Manassas, VA) were maintained in DMEM supplemented with 5% FCS at 9% CO2. The rVVs, M50 (negative control), hairpin (HP)19 full-length chimeric protein (termed NP/S), HP17 NP/S, HP0 NP/S, and (M)SIINFEKL have been previously described (13). Expansion and titering was performed on 143B HuTK- cells.
ELISPOT analysis
Mice were immunized i.p. with either 107
PFU or the indicated dose of the various rVVs. At the indicated times,
postinfection spleens were harvested and IFN- ELISPOT performed
essentially as described (13). As stimulators,
L-Kb cells were pulsed for 1 h with
10-8 M SIINFEKL (aa 257–264 of chicken OVA) in
the presence of 3.3 µg/ml 
2-microglobulin
(Scripps Laboratories, La Jolla, CA). The VV-specific T cell response
was assessed using modified vaccinia Ankara-infected
L-Kb cells as stimulators as described
(13). To normalize SIINFEKL-specific responses, the
average VV-specific response from all mice in a given experiment was
determined. The fold difference from the mean VV response was
calculated for each rVV-induced response (fold difference =
(average VV - individual VV)/individual VV). The corresponding
ELISPOT-determined SIINFEKL-specific T cell number was then multiplied
by the appropriate VV fold difference from mean to obtain a normalized
epitope-specific population size. Any mice for which the VV fold
difference from mean exceeded 3.0 (or below -3.0) were excluded from
the analysis.
Flow cytometry
A total of 106 spleen cells were stained with anti-CD8 (53–6.7, BD PharMingen, San Diego, CA), in some cases, anti-CD44 (IM7, BD PharMingen) or anti-CD69 (H1.2F3, BD PharMingen), and MHC class I/peptide tetramers of H-2Kb/SIINFEKL or an irrelevant tetramer, H-2Kd/influenza NP147–155, for 30–60 min at 4°C. Cells were washed three times with PBS/0.1% BSA + azide and resuspended in 2% paraformaldehyde before examining by flow cytometry in the Kimmel Cancer Center Flow Cytometry Facility (Thomas Jefferson University, Philadelphia, PA). Data were analyzed using WinMDI software (Scripps Laboratories).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We have developed a system to modulate Ag expression from a
constant dose of rVV by inserting thermostable duplex barriers, or HP,
of different sizes between the promoter and primary initiation codon of
the Ag of interest (13, 15, 16). The larger the HP, the
lower the level of Ag produced and cell-surface epitope expressed both
in vitro and in vivo (13). In the studies described below
we have examined the response to the
H-2Kb-restricted
OVA257–264 epitope (single letters SIINFEKL)
from chicken OVA when expressed in an NP/S alone, when NP/S is
expressed behind a HP, or when the SIINFEKL epitope is expressed by a
minigene (13). NP/S is composed of full-length influenza A
PR/8/34 nucleoprotein into which SIINFEKL was inserted at amino acid
position 366. Three SIINFEKL-expressing rVVs (and a negative control)
were used for most of the experiments (see Table I
). These recombinants were chosen to
examine the generation of epitope-specific CTL memory following
expression of low (HP19/NP/S), high (HP0/NP/S), and excessive
((M)SIINFEKL) levels of epitope. Using these rVVs, it is possible to
investigate the influence of epitope expression level on CTL memory
generation in vivo over a wide range (>75-fold) of epitope levels
without changing the infectious dose of virus (13).
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One advantage of the rVV HP system is that the anti-VV
response can be monitored ensuring that observed changes in
epitope-specific responses are not due to major differences in the
level of infection or overall antiviral immune response. In fact,
during the course of priming experiments using various rVVs, we noted
some minor variation in the magnitude of the overall T cell response to
VV (Fig. 1A). The reason for
this variation is unknown, but it is unlikely to be a result of the
expression of the inserted T cell epitope. First, no consistent pattern
of variation was observed between different rVVs. Second, as
illustrated in Fig. 1B, the magnitude and kinetics of the
anti-VV response is similar for all four rVVs described above.
However, it is important to determine how subtle differences in the
overall anti-VV immune response impacts the SIINFEKL-specific
population. If this variation occurs in a predictable manner, affecting
both the epitope-specific and virus-specific responses equally, then
epitope-specific populations can be accurately analyzed and
epitope-specific responses can be normalized according to the level of
VV-specific priming.
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ELISPOT analysis at each priming dose. As shown
in Fig. 1
C, there is a strong correlation between the
magnitude of the VV-specific response and the magnitude of the
SIINFEKL-specific response. When these data are converted to percent
maximal response the slope of the best fit linear regression curve
approaches 1.0, indicating that the changes in the epitope-specific and
overall antiviral T cell response are directly proportional when viral
dose is altered (data not shown). This demonstrates that subtle
variations in the total virus-specific response will have minor, but
predictable, impact upon the SIINFEKL-specific response. As a
result, the number of epitope-specific cells/spleen in a given
experiment can be normalized according to the number of VV-specific
cells/spleen detected. Fig. 1D shows the SIINFEKL-specific
response measured by IFN- ELISPOT from the same mice as represented
in Fig. 1A both before and after normalization at the peak
of the response (day 7) and in the memory phase (day 30). An arbitrary
cutoff of a 3-fold difference from mean VV response was used to
eliminate from consideration extreme cases for which the relationship
shown in Fig. 1C may not hold. Unless otherwise stated, the
following ELISPOT data have been normalized based on the number of
VV-specific cells/spleen, and in all cases multiple experiments yielded
similar results. In no case did normalization alter the hierarchy of
the SIINFEKL-specific responses to the different rVVs used in this
study (data not shown). The impact of epitope expression levels on the magnitude of CTL memory
The rVV HP system was used to express low (HP19), high (HP0), or
excessive (MSIINFEKL) levels of epitope and the sizes of the
epitope-specific and VV-specific populations at the peak and memory
phases were quantitated. Responses were examined either 7 or 8 days
following priming for the peak and >30 days postinoculation for the
memory response. The number of epitope-specific cells at the peak and
during memory was quantitated using both functional IFN- ELISPOT
analysis (Fig. 2A) and
staining with soluble MHC/peptide tetramers of
Kb/SIINFEKL (Fig. 2, B and
C). This latter analysis allows both the frequency (Fig. 2B) and absolute number (Fig. 2C) of
epitope-specific cells to be determined by flow cytometry (1, 17). The magnitude of the SIINFEKL-specific response
detected both functionally (Fig. 2A) and by MHC tetramer
staining (Fig. 2, B and C) at the peak of the
response closely parallels the level of epitope expression expected
from the rVV panel (see Table I). HP19, HP0, and (M)SIINFEKL elicit
progressively larger SIINFEKL-specific CTL populations at this
time. When the memory phase was examined, the relationship between the
size of the populations primed by HP19 and HP0 is maintained
whether examined by IFN- ELISPOT or tetramer staining. Despite
expressing a higher level of epitope and stimulating the largest
anti-SIINFEKL population at the peak, the minigene rVV elicits
a SIINFEKL-specific memory population that is smaller than that
elicited by HP0 (
2- to 4-fold) as detected by IFN- ELISPOT.
This is in agreement with our previous observation that the priming
with (M)SIINFEKL rVV results in a smaller response than HP0 as detected
by functional readouts except at early time points
(13). Interestingly, the response to (M)SIINFEKL is of
similar size, or even slightly larger, relative to HP0 responses, when
measured using MHC tetramer staining. Therefore, tetramer staining
indicates that significantly more memory cells are present following
minigene priming than are detected functionally.
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To examine more carefully the kinetics of the SIINFEKL-specific
response following priming with viruses expressing different levels of
epitope, IFN- ELISPOT and Kb/SIINFEKL tetramer
staining were performed at several times during both the acute and
memory phases of the response to rVV infection. Fig. 3 shows the number of SIINFEKL-specific
cells/spleen detected by both techniques over time. Control virus
(M50)-elicited responses were at or below the limits of detection for
both ELISPOT and tetramer staining except at early time points in
ELISPOT analysis when VV Ags from the original viral inoculum may still
be present (data not shown). As demonstrated in Fig. 3A, the
size of the epitope-specific population generated by HP19 is 1.5- to
5-fold lower than that elicited by HP0 at all time points. This is true
whether measured using IFN- ELISPOT analysis or by MHC/peptide
tetramer staining. In comparing the responses generated by the two
higher expressing constructs, HP0 and (M)SIINFEKL, it is apparent that
they are essentially equivalent by tetramer analysis. (Fig. 3B). They are also equivalent by IFN- ELISPOT analysis at
all points during the first week of the response. However, following
the peak (day 7), there is clearly a divergence, with the persistence
of many more IFN--producing cells following HP0 inocululation than
(M)SIINFEKL inoculation (Fig. 3A). This is true even at an
early point (day 14) during the generation of memory and by day 30 the
(M)SIINFEKL-induced response, measured by ELISPOT, is 4-fold lower
than that generated by HP0 rVV. The difference between direct detection
using tetramers and functional detection of (M)SIINFEKL-primed T cells
using IFN- ELISPOT analysis is further illustrated in Table II which shows the percent of
Kb/SIINFEKL tetramer-staining cells detected by
IFN- ELISPOT at the peak and memory time points as well as the peak
to memory ratio following HP rVV priming. The peak to memory ratios
illustrate that 10–15% of the SIINFEKL-specific T cells survive
into memory following HP19 or HP0 priming, but only 3.5% survive
following (M)SIINFEKL priming. Importantly, the fraction of the
VV-specific response that survives the death phase is similar for all
three constructs. In contrast to the ELISPOT data, there is no major
difference in the magnitude of contraction of the SIINFEKL-specific
response generated by the three constructs from peak to memory measured
by tetramer staining. These results illustrate that following
(M)SIINFEKL rVV priming, a lower fraction of the
tetramer+ memory population is detected
functionally than is detected following HP0 or HP19 priming.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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ELISPOT. With respect
to low (HP19) and high (HP0) epitope expression levels, our results are
consistent with previous studies that have illustrated a relationship
between initial virus-specific CTL burst size and the size of the
resulting memory population (1, 3, 10). In addition, we
demonstrate here that epitope levels during primary CTL stimulation can
be a major determinant of epitope-specific T cell memory size.
An advantage of the rVV approach is that the T cell response to the
entire virus and the epitope-specific response can be assessed in
parallel allowing the normalization of epitope-specific responses based
on the level of VV-specific priming. This approach also allows the
determination of the fraction of the total antiviral response that is
epitope-specific. The SIINFEKL-specific population generated by HP19 is
nearly 1/70 the VV-specific population, while that induced by HP0 is
1/11 at the memory time point, indicating the potential influence of
epitope levels on immunodominance. The ability of changes in epitope
levels to alter the fraction of the total response specific for
SIINFEKL is remarkable when it is considered that VV has the capacity
to express 200 proteins (18, 19) and clearly stimulates
a potent T cell response on its own.
Increasing epitope expression from high to excessive levels does not
significantly increase the number of SIINFEKL-specific cells detected
at the peak. However, functional IFN- ELISPOT analysis alone
suggests that minigene priming results in a smaller memory population,
in apparent contradiction with the expected correlation between the
burst size and memory size. However, ELISPOT analysis cannot determine
whether SIINFEKL-specific cells have been eliminated or whether they
persist in some altered or anergic state following minigene priming.
Given that the tetramer staining more accurately represents
the size of the population induced by (M)SIINFEKL, the dichotomy
between functional and structural detection may indicate a change in
the quality of the memory population generated by the minigene rVV. Our
results are an interesting contrast to the recent reports of
tetramer-negative, but functional, epitope-specific CD8+ T
cells (20, 21). It will be of great interest to
identify the factors that determine the widely disparate states that
memory CD8+ T cells are capable of achieving. One
possible explanation for the reduced functional detection of
(M)SIINFEKL-primed T cells is that they have become nonfunctional as a
result of overstimulation or inappropriate stimulation. Nonfunctional,
anergic, or "exhausted" CTLs have been described during chronic
viral infections or malignant transformation (22, 23, 24, 25).
However, such functionally incapable cells appear to arise only when
continued chronic antigenic stimulation can occur. Because VV causes an
acute infection (31, 32), Ag is unlikely to remain in an
immunogenic form capable of extended stimulation and exhaustion of
epitope-specific cells. Indeed, in contrast to other nonfunctional T
cells (22, 23, 24, 25), all tetramer-staining cells detected
following the peak of minigene rVV priming express low levels of the
early activation Ag, CD69 (data not shown), consistent with the absence
of continued antigenic stimulation. A second possible reason for the
decrease in detectable IFN--producing minigene-primed T cells is
immune deviation. Excessive epitope levels may result in a skewing of
the response from predominantly IFN- producing Tc1 cells to IL-10
producing Tc2 cells (26, 27). However, no IL-10 producing
SIINFEKL-specific cells can be detected by ELISPOT
following minigene priming (data not shown). It is also possible that
the form of the Ag expressed (full-length protein vs the
minigene-encoded epitope) influences functional CD8 T cell induction or
maintenance. For example, cross presentation may occur preferentially
for one form (e.g., peptides carried by heat shock proteins) leading to
differential usage of professional APC. However, a minigene rVV
construct expressing the influenza NP50–57
epitope primes for a similar or larger functional epitope-specific
response in C3H mice than does rVV expressing full-length NP
(13 and data not shown). Thus, while direct comparison of
the influence of Ag form vs epitope level will be an important area of
future investigation using the rVV HP system, we conclude that under
the conditions used, excessive epitope production is the basis for
development of the
tetramer+/IFN--
memory T cell population. It should also be noted that results similar
to ours have been reported by Bullock et al. (14), where a
decrease in the generation of functional CD8+ T
cells was noted using dendritic cells coated with increasing
concentrations of peptide alone.
Another interpretation of these results is that the high level of
epitope expressed by (M)SIINFEKL results in qualitatively inferior
memory cells that are less efficiently detected by IFN- ELISPOT
analysis at the concentrations of synthetic peptide that were used
(10-8 M). It has been suggested that competition
between T cells for antigenic stimulation may lead to selection of
particular clones entering the response (28, 29). It is
possible that excessive epitope expression could result in increased
recruitment of low-affinity T cells, and that these cells are more
easily detected functionally as highly activated effectors at the peak
than as resting memory cells. Alternatively, a recent study suggests
that differences in functional avidity can occur as a result of altered
signal transduction due to changes in the level of Lck expression
(30). It should be noted that similar ELISPOT results were
observed using EL-4 cells transfected with OVA as APC which present the
SIINFEKL epitope with high efficiency (13 and data not
shown). In addition, we have observed loss of effector function
(cytolysis) following (M)SIINFEKL vac immunization when synthetic
peptide was used at 10-6 M (13).
These results are consistent with the generation of (M)SIINFEKL-primed
T cells that are essentially nonfunctional rather than responsive only
when higher doses of peptide are used. Experiments are underway to
elucidate the basis for the striking differences between CTL
populations elicited under conditions of high and excessive epitope
availability.
Effective CTL memory is a major goal of vaccines against intracellular pathogens. The ability of epitope-specific memory T cells to control or eliminate an infection is likely a result of both the quantity and quality of the antiviral memory CTL population available. We have demonstrated that epitope expression level during initial T cell priming is a major determinant of the size of the resulting memory pool by using rVV generating low (HP19) and high (HP0) epitope levels in vivo. Importantly, the highest level of expression achieved using a minigene ((M)SIINFEKL) may not represent the optimal conditions for inducing an antiviral CTL population. Thus, modulation of MHC class I-restricted epitope expression levels is an important consideration in the design of vaccines.
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Acknowledgments |
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Footnotes |
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2 Current address: Department of Microbiology and Immunology, Emory Vaccine Center, Emory University, Atlanta, GA 30322.
3 Current address: Merck and Co., WP16A-99, West Point, PA 19486.
4 Address correspondence and reprint requests to Dr. Laurence C. Eisenlohr, Department of Microbiology and Immunology, Kimmel Cancer Institute, Thomas Jefferson University, Philadelphia, PA 19107. E-mail address: L_Eisenlohr{at}hendrix.jci.tju.edu
5 Abbreviations used in this paper: VV, vaccinia virus; HP, hairpin.
Received for publication November 16, 2001. Accepted for publication February 26, 2002.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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T. S. Kim and S. Perlman Protection Against CTL Escape and Clinical Disease in a Murine Model of Virus Persistence J. Immunol., August 15, 2003; 171(4): 2006 - 2013. [Abstract] [Full Text] [PDF]
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 S. Gottschalk, O. L. Edwards, U. Sili, M. H. Huls, T. Goltsova, A. R. Davis, H. E. Heslop, and C. M. Rooney Generating CTLs against the subdominant Epstein-Barr virus LMP1 antigen for the adoptive immunotherapy of EBV-associated malignancies Blood, March 1, 2003; 101(5): 1905 - 1912. [Abstract] [Full Text] [PDF]
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T. N. J. Bullock, D. W. Mullins, and V. H. Engelhard Antigen Density Presented By Dendritic Cells In Vivo Differentially Affects the Number and Avidity of Primary, Memory, and Recall CD8+ T Cells J. Immunol., February 15, 2003; 170(4): 1822 - 1829. [Abstract] [Full Text] [PDF]
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